Heteroaryl substituted pyrazoles

ABSTRACT

Compounds of formula (I), processes for their preparation and their use as pharmaceuticals.

FIELD OF APPLICATION OF THE INVENTION

The invention relates to substituted benzylpyrazole compounds, a processfor their production and the use thereof.

BACKGROUND OF THE INVENTION

One of the most fundamental characteristics of cancer cells is theirability to sustain chronic proliferation whereas in normal tissues theentry into and progression through the cell division cycle is tightlycontrolled to ensure a homeostasis of cell number and maintenance ofnormal tissue function. Loss of proliferation control was emphasized asone of the six hallmarks of cancer [Hanahan D and Weinberg R A, Cell100, 57, 2000; Hanahan D and Weinberg R A, Cell 144, 646, 2011].

The eukaryotic cell division cycle (or cell cycle) ensures theduplication of the genome and its distribution to the daughter cells bypassing through a coordinated and regulated sequence of events. The cellcycle is divided into four successive phases:

1. The G1 phase represents the time before the DNA replication, in whichthe cell grows and is sensitive to external stimuli.2. In the S phase the cell replicates its DNA, and3. in the G2 phase preparations are made for entry into mitosis.4. In mitosis (M phase), the duplicated chromosomes get separatedsupported by a spindle device built from microtubules, and cell divisioninto two daughter cells is completed.

To ensure the extraordinary high fidelity required for an accuratedistribution of the chromosomes to the daughter cells, the passagethrough the cell cycle is strictly regulated and controlled. The enzymesthat are necessary for the progression through the cycle must beactivated at the correct time and are also turned off again as soon asthe corresponding phase is passed. Corresponding control points(“checkpoints”) stop or delay the progression through the cell cycle ifDNA damage is detected, or the DNA replication or the creation of thespindle device is not yet completed. The mitotic checkpoint (also knownas spindle checkpoint or spindle assembly checkpoint) controls theaccurate attachment of mircrotubules of the spindle device to thekinetochors (the attachment site for microtubules) of the duplicatedchromosomes. The mitotic checkpoint is active as long as unattachedkinetochores are present and generates a wait-signal to give thedividing cell the time to ensure that each kinetochore is attached to aspindle pole, and to correct attachment errors. Thus the mitoticcheckpoint prevents a mitotic cell from completing cell division withunattached or erroneously attached chromosomes [Suijkerbuijk S J andKops G J, Biochem. Biophys. Acta 1786, 24, 2008; Musacchio A and SalmonE D, Nat. Rev. Mol. Cell. Biol. 8, 379, 2007]. Once all kinetochores areattached with the mitotic spindle poles in a correct bipolar(amphitelic) fashion, the checkpoint is satisfied and the cell entersanaphase and proceeds through mitosis.

The mitotic checkpoint is established by a complex network of a numberof essential proteins, including members of the MAD (mitotic arrestdeficient, MAD 1-3) and Bub (Budding uninhibited by benzimidazole, Bub1-3) families, Mps1 kinase, cdc20, as well as other components [reviewedin Bolanos-Garcia V M and Blundell T L, Trends Biochem. Sci. 36, 141,2010], many of these being over-expressed in proliferating cells (e.g.cancer cells) and tissues [Yuan B et al., Clin. Cancer Res. 12, 405,2006]. The major function of an unsatisfied mitotic checkpoint is tokeep the anaphase-promoting complex/cyclosome (APC/C) in an inactivestate. As soon as the checkpoint gets satisfied the APC/Cubiquitin-ligase targets cyclin B and securin for proteolyticdegradation leading to separation of the paired chromosomes and exitfrom mitosis.

Inactive mutations of the Ser/Thr kinase Bub1 prevented the delay inprogression through mitosis upon treatment of cells of the yeast S.cerevisiae with microtubule-destabilizing drugs, which led to theidentification of Bub1 as a mitotic checkpoint protein [Roberts B T etal., Mol. Cell Biol., 14, 8282, 1994]. A number of recent publicationsprovide evidence that Bub1 plays multiple roles during mitosis which,have been reviewed by Elowe [Elowe S, Mol. Cell. Biol. 31, 3085, 2011].In particular, Bub1 is one of the first mitotic checkpoint proteins thatbinds to the kinetochores of duplicated chromosomes and probably acts asa scaffolding protein to constitute the mitotic checkpoint complex.Furthermore, via phosphorylation of histone H2A, Bub1 localizes theprotein shugoshin to the centromeric region of the chromosomes toprevent premature segregation of the paired chromosomes [Kawashima etal. Science 327, 172, 2010]. In addition, together with a Thr-3phosphorylated Histone H3 the shugoshin protein functions as a bindingsite for the chromosomal passenger complex which includes the proteinssurvivin, borealin, INCENP and Aurora B. The chromosomal passengercomplex is seen as a tension sensor within the mitotic checkpointmechanism, which dissolves erroneously formed microtubule-kinetochorattachments such as syntelic (both sister kinetochors are attached toone spindle pole) or merotelic (one kinetochor is attached to twospindle poles) attachments [Watanabe Y, Cold Spring Harb. Symp. Quant.Biol. 75, 419, 2010].

Incomplete mitotic checkpoint function has been linked with aneuploidyand tumourigenesis [Weaver B A and Cleveland D W, Cancer Res. 67, 10103,2007; King R W, Biochim Biophys Acta 1786, 4, 2008]. In contrast,complete inhibition of the mitotic checkpoint has been recognised toresult in severe chromosome missegregation and induction of apoptosis intumour cells [Kops G J et al., Nature Rev. Cancer 5, 773, 2005; SchmidtM and Medema R H, Cell Cycle 5, 159, 2006; Schmidt M and Bastians H,Drug Res. Updates 10, 162, 2007]. Thus, mitotic checkpoint abrogationthrough pharmacological inhibition of components of the mitoticcheckpoint, such as Bub1 kinase, represents a new approach for thetreatment of proliferative disorders, including solid tumours such ascarcinomas, sarcomas, leukaemias and lymphoid malignancies or otherdisorders, associated with uncontrolled cellular proliferation.

The present invention relates to chemical compounds that inhibit Bub1kinase.

Established anti-mitotic drugs such as vinca alkaloids, taxanes orepothilones activate the mitotic checkpoint, inducing a mitotic arresteither by stabilising or destabilising microtubule dynamics. This arrestprevents separation of the duplicated chromosomes to form the twodaughter cells. Prolonged arrest in mitosis forces a cell either intomitotic exit without cytokinesis (mitotic slippage or adaption) or intomitotic catastrophe leading to cell death [Rieder C L and Maiato H, Dev.Cell 7, 637, 2004]. In contrast, inhibitors of Bub1 prevent theestablishment and/or functionality of the mitotic checkpoint and/ormicrotubule-kinetochor attachment error correction mechanisms, whichfinally results in severe chromosomal missegregation, induction ofapoptosis and cell death.

These findings suggest that Bub1 inhibitors should be of therapeuticvalue for the treatment of proliferative disorders associated withenhanced uncontrolled proliferative cellular processes such as, forexample, cancer, inflammation, arthritis, viral diseases, cardiovasculardiseases, or fungal diseases in a warm-blooded animal such as man.

WO 2013/050438 discloses substituted benzylindazole derivatives whichare Bub1 kinase inhibitors.

WO 2013/092512 discloses substituted benzylpyrazole derivatives whichare Bub1 kinase inhibitors.

WO 2013/167698 discloses substituted benzylcycloalkylpyrazoles, whichare Bub1 kinase inhibitors.

WO 2014/147144 discloses diaminoheteroaryl substituted indazolederivatives, which are Bub1 kinase inhibitors.

WO 2014/147203 discloses heteroaryl substituted indazole derivatives,which are Bub1 kinase inhibitors.

WO 2014/147204 discloses heteroaryl substituted indazole derivatives,which are Bub1 kinase inhibitors.

Due to the fact that especially cancer disease as being expressed byuncontrolled proliferative cellular processes in tissues of differentorgans of the human- or animal body still is not considered to be acontrolled disease in that sufficient drug therapies already exist,there is a strong need to provide further new therapeutically usefuldrugs, preferably inhibiting new targets and providing new therapeuticoptions (e.g. drugs with improved pharmacological properties).

DESCRIPTION OF THE INVENTION

Therefore, inhibitors of Bub1 represent valuable compounds that shouldcomplement therapeutic options either as single agents or in combinationwith other drugs.

In accordance with a first aspect, the invention relates to compounds offormula (I)

in which

represents a

group, whereby the * is the point of attachment,

-   -   wherein        -   X¹ is NR¹⁸, O, or S,        -   X² is CR⁴, or N,        -   X³ is NR¹⁸, O, or S,        -   X⁴ is CR⁴, or N,        -   X⁵ is CR⁴, or N,        -   X⁶ is CR⁴,        -   X⁷ is NR¹⁸,        -   X⁸ is CR⁴,        -   X⁹ is NR¹⁸, O, or S,        -   X¹⁰ is CR⁴, or N,        -   X¹¹ is CR⁴, or N,        -   X¹² is CR⁴, or N,    -   in which group        -   E represents a

-   -   -    group,            -   whereby the * is the point of attachment,            -   T is CH, CR¹⁷ or N,            -   Y is CH, CR¹⁷ or N,            -   whereby one or both of T and Y represent CH or CR¹⁷,                and

-   R¹/R² are independently from each other hydrogen, or halogen,

-   R³ is independently from each other 1-6C-alkyl, 1-6C-alkoxy,    halogen, 2-6C-alkenyl, 3-6C-cycloalkyl, 1-6C-haloalkoxy, or C(O)OH,

-   n is 0, 1, 2 or 3,    -   or        -   R³ is -(1-6C-alkylene)-S—R¹⁴, -(1-6C-alkylene)-S(O)—R¹⁴,            -(1-6C-alkylene)-S(O)₂—R¹⁴,            -(1-6C-alkylene)-S(═O)(═NR¹⁵)R¹⁴, —O-(1-6C-alkylene)-S—R¹⁴,            —O-(1-6C-alkylene)-S(O)—R¹⁴, —O-(1-6C-alkylene)-S(O)₂—R¹⁴,            or —O-(1-6C-alkylene)-S(═O)(═NR¹⁵)R¹⁴,        -   and    -   n is 1,

-   R⁴ is independently from each other    -   (a) hydrogen,    -   (b) hydroxy,    -   (c) 1-6C-alkoxy optionally substituted with        -   (c1) 1 or 2 hydroxy,        -   (c2) —NR⁹R¹⁰,        -   (c3) —S—R¹⁴,        -   (c4) —S(O)—R¹⁴,        -   (c5) —S(O)₂—R¹⁴,        -   (c6) —S(═O)(═NR¹⁵)R¹⁴,        -   (c7) —S(O)₂NR⁹R¹⁰,    -   (d)

-   -    whereby the * is the point of attachment,    -   (e)

-   -    whereby the * is the point of attachment,    -   (f) cyano, or    -   (g) —S(O)₂-(1-4C-alkyl),

-   R⁵ is    -   (a) hydrogen,    -   (b) 2-6C-hydroxyalkyl,    -   (c)

-   -    whereby the * is the point of attachment,    -   (d) —C(O)-(1-6C-alkyl),    -   (e) —C(O)-(1-6C-alkylene)-O-(1-6C-alkyl), or    -   (f) —C(O)-(1-6C-alkylene)-O-(1-6C-alkylene)-O-(1-6C-alkyl),

-   R⁶ is independently from each other halogen, cyano, —C(O)NR¹¹R¹², or    —C(O)OR¹³,

-   m is 0, 1, or 2,

-   R⁷ is hydrogen, halogen, cyano, 1-6C-alkyl, 2-6C-alkenyl,    1-6C-alkoxy, 1-6C-haloalkoxy, 3-6C-cycloalkyl, —C(O)NR¹¹R¹² or    —NR⁹R¹⁰,

-   R⁸ is hydrogen, halogen, cyano, 1-6C-alkyl, 2-6C-alkenyl,    1-6C-alkoxy, 1-6C-haloalkoxy, 3-6C-cycloalkyl or —NR⁹R¹⁰,    -   or

-   R⁷ and R⁸ form together with the two carbon atoms to which they are    attached a 6-membered aromatic ring, which is optionally substituted    independently one or more times with halogen or 1-3C-alkyl,    -   or

-   R⁷ and R⁸ form together a n-propylene or a n-butylene group,

-   R⁹, R¹⁰ are independently from each other hydrogen, 1-6C-alkyl or    together with the nitrogen atom to which they are attached form a    4-6-membered heterocyclic ring optionally containing one further    heteroatom selected from the group consisting of O, S or N,

-   R¹¹, R¹² are independently from each other hydrogen, 1-6C-alkyl,    2-6C-hydroxyalkyl, or (1-4C-alkyl)-S(O)₂-(1-4C-alkyl),

-   R¹³ is independently from each other hydrogen or 1-4C-alkyl,

-   R¹⁴ is independently from each other a group selected from    1-6C-alkyl, 3-7C-cycloalkyl, phenyl and benzyl,    -   wherein said group is optionally substituted with one or two or        three substituents, identically or differently, selected from        the group of hydroxy, halogen, or —NR⁹R¹⁰,

-   R¹⁵ is independently from each other hydrogen, cyano, or —C(O)R¹⁶,

-   R¹⁶ is 1-6C-alkyl, or 1-6C-haloalkyl,

-   R¹⁷ is independently from each other halogen, cyano, —C(O)NR¹¹R¹²,    or —C(O)OR¹³,

-   R¹⁸ is    -   (a) hydrogen,    -   (b) 1-6C-alkyl optionally substituted with        -   (b1) 1 or 2 hydroxy,        -   (b2) 1-6C-alkoxy,        -   (b3) —C(O)OR¹³,        -   (b4) —C(O)NR¹¹R¹²,        -   (b5) —NR⁹R¹⁰,        -   (b6) —S—R¹⁴,        -   (b7) —S(O)—R¹⁴,        -   (b8) —S(O)₂—R¹⁴,        -   (b9) —S(═O)(═NR¹⁵)R¹⁴,        -   (b10) —S(O)₂NR⁹R¹⁰,    -   (c) —S(O)₂-(1-4C-alkyl),    -   (d) —C(O)-(1-6C-alkyl),        or an N-oxide, a salt, a tautomer or a stereoisomer of said        compound, or a salt of said N-oxide, tautomer or stereoisomer.

In accordance with a second aspect, the invention relates to compoundsof formula (I)

wherein

represents a

group, whereby the * is the point of attachment,

-   -   wherein        -   X¹ is NR¹⁸, O, or S,        -   X² is CR⁴, or N,        -   X³ is NR¹⁸, O, or S,        -   X⁴ is CR⁴, or N,        -   X⁵ is CR⁴, or N,        -   X⁶ is CR⁴,        -   X⁷ is NR¹⁸,        -   X⁸ is CR⁴,        -   X⁹ is NR¹⁸, O, or S,        -   X¹⁰ is CR⁴, or N,        -   X¹¹ is CR⁴, or N,        -   X¹² is CR⁴, or N,    -   in which group        -   E represents a

-   -   -    group,            whereby the * is the point of attachment,

T is CH, CR¹⁷ or N, Y is CH, CR¹⁷ or N,

whereby one or both of T and Y represent CH or CR¹⁷,and

-   R¹/R² are independently from each other hydrogen, or halogen,-   R³ is independently from each other 1-3C-alkoxy,-   n is 0, 1, 2, or 3,    -   or        -   R³ is -(1-4C-alkylene)-S—R¹⁴, -(1-4C-alkylene)-S(O)—R¹⁴,            -(1-4C-alkylene)-S(O)₂—R¹⁴,            -(1-4C-alkylene)-S(═O)(═NR¹⁵)R¹⁴, —O-(1-4C-alkylene)-S—R¹⁴,            —O-(1-4C-alkylene)-S(O)—R¹⁴, —O-(1-4C-alkylene)-S(O)₂—R¹⁴,            or —O-(1-4C-alkylene)-S(═O)(═NR¹⁵)R¹⁴,        -   and        -   n is 1,-   R⁴ is independently from each other    -   (a) hydrogen,    -   (b) hydroxy,    -   (c) 1-4C-alkoxy optionally substituted with        -   (c1) 1 or 2 hydroxy,        -   (c2) —NR⁹R¹⁰,        -   (c3) —S—R¹⁴,        -   (c4) —S(O)—R¹⁴,        -   (c5) —S(O)₂—R¹⁴,        -   (c6) —S(═O)(═NR¹⁵)R¹⁴,        -   (c7) —S(O)₂NR⁹R¹⁰,    -   (f) cyano, or    -   (g) —S(O)₂-(1-4C-alkyl),-   R⁵ is hydrogen,    -   R⁶ is independently from each other halogen, cyano,        —C(O)NR¹¹R¹², or —C(O)OR¹³,-   m is 0, 1, or 2,-   R⁷ is hydrogen, halogen, cyano, 1-3C-alkyl, 2-3C-alkenyl,    1-3C-alkoxy, 1-3C-haloalkoxy, 3-6C-cycloalkyl, —C(O)NR¹¹R¹² or    —NR⁹R¹⁰,-   R⁸ is hydrogen, halogen, cyano, 1-3C-alkyl, 2-3C-alkenyl,    1-3C-alkoxy, 1-3C-haloalkoxy, 3-6C-cycloalkyl or —NR⁹R¹⁰,    -   or-   R⁷ and R⁸ form together with the two carbon atoms to which they are    attached a 6-membered aromatic ring, which is optionally substituted    independently one or more times with halogen or 1-3C-alkyl,-   R⁹, R¹⁰ are independently from each other hydrogen or 1-3C-alkyl, or    together with the nitrogen atom to which they are attached form a    4-6-membered heterocyclic ring optionally containing one further    heteroatom selected from the group consisting of O, S or N,-   R¹¹, R¹² are independently from each other hydrogen, 1-3C-alkyl, or    2-3C-hydroxyalkyl,-   R¹³ is independently from each other hydrogen or 1-3C-alkyl,-   R¹⁴ is independently from each other a group selected from    1-3C-alkyl, and 3-7C-cycloalkyl,-   R¹⁵ is independently from each other hydrogen, cyano, or —C(O)R¹⁶,-   R¹⁶ is methyl, or trifluoromethyl,-   R¹⁷ is independently from each other halogen, cyano, —C(O)NR¹¹R¹²,    or —C(O)OR¹³,-   R¹⁸ is    -   (a) hydrogen,    -   (b) 1-4C-alkyl optionally substituted with        -   (b1) 1 or 2 hydroxy,        -   (b2) 1-3C-alkoxy,        -   (b3) —C(O)OR¹³,        -   (b4) —C(O)NR¹¹R¹²,        -   (b5) —NR⁹R¹⁰,        -   (b6) —S—R¹⁴,        -   (b7) —S(O)—R¹⁴,        -   (b8) —S(O)₂—R¹⁴,        -   (b9) —S(═O)(═NR¹⁵)R¹⁴,        -   (b10) —S(O)₂NR⁹R¹⁰,    -   (c) —S(O)₂-(1-4C-alkyl),    -   (d) —C(O)-(1-3C-alkyl),        or an N-oxide, a salt, a tautomer or a stereoisomer of said        compound, or a salt of said N-oxide, tautomer or stereoisomer.

Another aspect of the invention are compounds of formula (I),

wherein

represents a

group, whereby the * is the point of attachment,

-   -   wherein        -   X¹ is NR¹⁸, O, or S,        -   X² is CR⁴, or N,        -   X³ is NR¹⁸, O, or S,        -   X⁴ is CR⁴, or N,        -   X⁵ is CR⁴, or N,        -   X⁶ is CR⁴,        -   X⁷ is NR¹⁸,        -   X⁸ is CR⁴,        -   X⁹ is NR¹⁸, O, or S,        -   X¹⁰ is CR⁴, or N,        -   X¹¹ is CR⁴, or N,        -   X¹² is CR⁴, or N,    -   in which group        -   E represents a

-   -   -    group,            -   whereby the * is the point of attachment,            -   T is CH, CR¹⁷ or N,            -   Y is CH, CR¹⁷ or N,                whereby one or both of T and Y represent CH or CR¹⁷,                and

-   R¹/R² are independently from each other hydrogen, or halogen,

-   R³ is 1-3C-alkoxy,

-   n is 0, or 1,

-   R⁴ is independently from each other    -   (a) hydrogen,    -   (c) 1-4C-alkoxy optionally substituted with        -   (c1) hydroxy,        -   (c3) —S—R¹⁴,        -   (c4) —S(O)—R¹⁴,        -   (c5) —S(O)₂—R¹⁴,        -   (c6) —S(═O)(═NR¹⁵)R¹⁴, or        -   (c7) —S(O)₂NR⁹R¹⁰,

-   R⁵ is hydrogen,

-   R⁶ is —C(O)NR¹¹R¹², or —C(O)OR¹³,

-   m is 0, or 1,

-   R⁷ is 3-6C-cycloalkyl,

-   R⁸ is 1-3C-alkyl,    -   or

-   R⁷ and R⁸ form together with the two carbon atoms to which they are    attached a 6-membered aromatic ring, which is optionally substituted    independently one or more times with halogen or 1-3C-alkyl,

-   R⁹, R¹⁰ are independently from each other hydrogen or 1-3C-alkyl, or    together with the nitrogen atom to which they are attached form a    4-6-membered heterocyclic ring optionally containing one further    heteroatom selected from the group consisting of O, S or N,

-   R¹¹, R¹² are independently from each other hydrogen, or 1-3C-alkyl,

-   R¹³ is independently from each other hydrogen or 1-3C-alkyl,

-   R¹⁴ is 1-3C-alkyl,

-   R¹⁵ is hydrogen,

-   R¹⁷ is independently from each other —C(O)NR¹¹R¹², or —C(O)OR¹³,

-   R¹⁸ is    -   (a) hydrogen,    -   (b) 1-4C-alkyl optionally substituted with        -   (b1) hydroxy,        -   (b2) 1-3C-alkoxy,        -   (b3) —C(O)OR¹³,        -   (b4) —C(O)NR¹¹R¹²,        -   (b5) —NR⁹R¹⁰,        -   (b6) —S—R¹⁴,        -   (b7) —S(O)—R¹⁴,        -   (b8) —S(O)₂—R¹⁴,        -   (b9) —S(═O)(═NR¹⁵)R¹⁴,    -   (d) —C(O)-(1-3C-alkyl),        or an N-oxide, a salt, a tautomer or a stereoisomer of said        compound, or a salt of said N-oxide, tautomer or stereoisomer.

A further aspect of the invention relates to compounds of formula (I)

wherein

represents a

group, whereby the * is the point of attachment,

-   -   wherein        -   X¹ is NR¹⁸, or S,        -   X² is CR⁴, or N,        -   X³ is NR¹⁸,        -   X⁴ is N,        -   X¹⁰ is CR⁴,        -   X¹¹ is CR⁴,        -   X¹² is N,    -   in which group        -   E represents a

-   -   -    group,            whereby the * is the point of attachment,

T is CH, Y is CH, or N,

and

-   R¹/R² are independently from each other hydrogen, or fluoro,-   R³ is ethoxy,-   n is 0, or 1,-   R⁴ is    -   (a) hydrogen,-   R⁵ is hydrogen,-   R⁶ is —C(O)OR¹³,-   m is 0, or 1,-   R⁷ is cyclopropyl,-   R⁸ is methyl,    -   or-   R⁷ and R⁸ form together with the two carbon atoms to which they are    attached a 6-membered aromatic ring,-   R⁹, R¹⁰ together with the nitrogen atom to which they are attached    form a morpholine ring-   R¹³ is independently from each other hydrogen or ethyl,-   R¹⁴ is methyl,-   R¹⁸ is    -   (a) hydrogen,    -   (b) 1-2C-alkyl optionally substituted with        -   (b1) hydroxy,        -   (b2) methoxy,        -   (b3) —C(O)OR¹³,        -   (b5) —NR⁹R¹⁰,        -   (b8) —S(O)₂—R¹⁴,    -   (d) acetyl,        or an N-oxide, a salt, a tautomer or a stereoisomer of said        compound, or a salt of said N-oxide, tautomer or stereoisomer.

A further aspect of the invention relates to compounds of formula (I)selected from the group consisting of:

-   5′-cyclopropyl-1′-(4-ethoxy-2,6-difluorobenzyl)-4′-methyl-1-[2-(morpholin-4-yl)-ethyl]-N-(pyrimidin-4-yl)-1H,1′H-3,3′-bipyrazol-5-amine,-   1-[5′-cyclopropyl-1′-(4-ethoxy-2,6-difluorobenzyl)-4′-methyl-5-(pyrimidin-4-ylamino)-1    H,1′H-3,3′-bipyrazol-1-yl]ethanone,-   [5′-cyclopropyl-1′-(4-ethoxy-2,6-difluorobenzyl)-4′-methyl-5-(pyrimidin-4-ylamino)-1    H,1′H-3,3′-bipyrazol-1-yl]acetic acid,-   5′-cyclopropyl-1′-(4-ethoxy-2,6-difluorobenzyl)-1,4′-di    methyl-N-(pyrimidin-4-yl)-1 H,1′H-3,3′-bipyrazol-5-amine,-   N-{3-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-1-(2-methoxyethyl)-1H-1,2,4-triazol-5-yl}pyrimidin-4-amine,-   5′-cyclopropyl-1′-(4-ethoxy-2,6-difluorobenzyl)-4′-methyl-1-[2-(methylsulfonyl)-ethyl]-N-(pyrimidin-4-yl)-1H,1′H-3,3′-bipyrazol-5-amine,-   5′-cyclopropyl-1′-(4-ethoxy-2,6-difluorobenzyl)-1,4′-di    methyl-N-(pyridin-4-yl)-1 H,1′H-3,3′-bipyrazol-5-amine,-   N-{3-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-1-(2-methoxyethyl)-1H-1,2,4-triazol-5-yl}pyridin-4-amine,-   2-{3-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-5-(pyridin-4-ylamino)-1H-1,2,4-triazol-1-yl}ethanol,-   N-{3-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl}pyridin-4-amine,-   ethyl    4-({3-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-1-(2-methoxyethyl)-1H-1,2,4-triazol-5-yl}amino)nicotinate,-   N-{3-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-1-(2-methoxyethyl)-1H-1,2,4-triazol-5-yl}pyridin-4-amine,-   N-{5-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl}pyridin-4-amine,-   N-{1-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-1H-pyrazol-4-yl}pyrimidin-4-amine,    and-   N-{3-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-1,2,4-thiadiazol-5-yl}pyridin-4-amine,    or an N-oxide, a salt, a tautomer or a stereoisomer of said    compound, or a salt of said N-oxide, tautomer or stereoisomer.

One aspect of the invention are compounds of formula (I) as described inthe examples, as characterized by their names in the title, as claimedin claim 5 and/or their structures as well as the subcombinations of allresidues specifically disclosed in the compounds of the examples.

Another aspect of the present invention are the intermediates used forthe synthesis of the compounds of formula (I) and the use of suchintermediates for the synthesis of the compounds of formula (I) or aN-oxide, a salt, a tautomer or a stereoisomer of said compound, or asalt of said N-oxide, tautomer or stereoisomer.

Further aspect of the invention are compounds of formula (I), which arepresent as their salts.

Another embodiment of the invention are compounds according to theclaims as disclosed in the Claims section wherein the definitions arelimited according to the preferred or more preferred definitions asdisclosed below or specifically or especially disclosed residues of theexemplified compounds and subcombinations thereof.

If embodiments of the invention as disclosed herein relate to compoundsof formula (I), it is understood that those embodiments refer to thecompounds of formula (I) as disclosed in any of the claims and theexamples.

A further aspect of the invention relates to compounds of formula (I)

wherein

represents a

group, whereby the * is the point of attachment,

-   -   wherein        -   X¹ is NR¹⁸, or S,        -   X² is CR⁴, or N,        -   X³ is NR¹⁸,        -   X⁴ is N,        -   X¹⁰ is CR⁴,        -   X¹¹ is CR⁴,        -   X¹² is N,    -   in which group        -   E represents a

-   -   -    group,            -   whereby the * is the point of attachment,            -   T is CH,            -   Y is CH, or N,                and

-   R¹/R² are independently of each other hydrogen, or halogen,

-   R³ is 1-6C-alkoxy,

-   n is 0, or 1,

-   R⁴ is hydrogen,

-   R⁵ is hydrogen,

-   R⁶ is C(O)OR¹³,

-   m is 0, or 1,

-   R⁷ is 3-6C-cycloalkyl,

-   R⁸ is 1-6C-alkyl,    -   or

-   R⁷ and R⁸ form together with the two carbon atoms to which they are    attached a 6-membered aromatic ring,

-   R⁹, R¹⁰ together with the nitrogen atom to which they are attached    form a 4-6-membered heterocyclic ring optionally containing one    further heteroatom selected from the group consisting of O,

-   R¹³ is hydrogen or 1-4C-alkyl,

-   R¹⁴ is 1-6C-alkyl,

-   R¹⁸ is    -   (a) hydrogen,    -   (b) 1-6C-alkyl optionally substituted with        -   (b1) hydroxy,        -   (b2) 1-6C-alkoxy,        -   (b3) —C(O)OR¹³,        -   (b5) —NR⁹R¹⁰,        -   (b8) —S(O)₂—R¹⁴,    -   (d) —C(O)-(1-6C-alkyl),        or an N-oxide, a salt, a tautomer or a stereoisomer of said        compound, or a salt of said N-oxide, tautomer or stereoisomer.

Another aspect of the invention are compounds of formula (I), as definedsupra, in Which

represents a

group, whereby the * is the point of attachment,

-   -   wherein        -   X¹ is NR¹⁸, O, or S,        -   X² is CR⁴, or N,        -   X³ is NR¹⁸, O, or S,        -   X⁴ is CR⁴, or N,        -   X⁵ is CR⁴, or N,        -   X⁶ is CR⁴,        -   X⁷ is NR¹⁸,        -   X⁸ is CR⁴,        -   X⁹ is NR¹⁸, O, or S,        -   X¹⁰ is CR⁴, or N,        -   X¹¹ is CR⁴, or N,        -   X¹² is CR⁴, or N,    -   in which group        -   E represents a

-   -   -    group,            -   whereby the * is the point of attachment,            -   T is CH, CR¹⁷ or N,            -   Y is CH, CR¹⁷ or N,            -   whereby one or both of T and Y represent CH or CR¹⁷.

Another aspect of the invention are compounds of formula (I), as definedsupra, in Which

represents a

group, whereby the * is the point of attachment,

-   -   wherein        -   X¹ is NR¹⁸, or S,        -   X² is CR⁴, or N,        -   X³ is NR¹⁸,        -   X⁴ is N,        -   X¹⁰ is CR⁴,        -   X¹¹ is CR⁴,        -   X¹² is N,    -   in which group        -   E represents a

-   -   -    group,            -   whereby the * is the point of attachment,            -   T is CH,            -   Y is CH, or N.

Another aspect of the invention are compounds of formula (I), as definedsupra, in Which

represents a

group, whereby the * is the point of attachment,

-   -   wherein        -   X¹ is NR¹⁸, or S,        -   X² is CR⁴, or N,    -   in which group        -   E represents a

-   -   -    group,            -   whereby the * is the point of attachment,            -   T is CH,            -   Y is CH, or N.

Another aspect of the invention are compounds of formula (I), as definedsupra, in Which

represents a

group, whereby the * is the point of attachment,

-   -   wherein        -   X³ is NR¹⁸,        -   X⁴ is N,    -   in which group        -   E represents a

-   -   -    group,            -   whereby the * is the point of attachment,            -   T is CH,            -   Y is CH, or N.

Another aspect of the invention are compounds of formula (I), as definedsupra, in Which

represents a

group, whereby the * is the point of attachment,

-   -   wherein        -   X¹⁰ is CR⁴,        -   X¹¹ is CR⁴,        -   X¹² is N,    -   in which group        -   E represents a

-   -   -    group,            -   whereby the * is the point of attachment,            -   T is CH,            -   Y is CH, or N.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹ is hydrogen, or halogen.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹ is hydrogen, or fluoro.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹ is hydrogen.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹ is fluoro.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R² is hydrogen, or halogen.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R² is hydrogen, or fluoro.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R² is hydrogen.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R² is fluoro.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R³ is 1-6C-alkyl, 1-6C-alkoxy, halogen, 2-6C-alkenyl,    3-6C-cycloalkyl, 1-6C-haloalkoxy, or C(O)OH.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R³ is 1-3C-alkoxy.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R³ is ethoxy.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   n is 0, 1, 2 or 3.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   n is 0, or 1.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   n is 1.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   n is 0.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R³ is -(1-6C-alkylene)-S—R¹⁴, -(1-6C-alkylene)-S(O)—R¹⁴,    -(1-6C-alkylene)-S(O)₂—R¹⁴, -(1-6C-alkylene)-S(═O)(═NR¹⁵)R¹⁴,    —O-(1-6C-alkylene)-S—R¹⁴, —O-(1-6C-alkylene)-S(O)—R¹⁴,    —O-(1-6C-alkylene)-S(O)₂—R¹⁴, or —O-(1-6C-alkylene)-S(═O)(═NR¹⁵)R¹⁴,    -   and    -   n is 1.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R³ is -(1-4C-alkylene)-S—R¹⁴, -(1-4C-alkylene)-S(O)—R¹⁴,    -(1-4C-alkylene)-S(O)₂—R¹⁴, -(1-4C-alkylene)-S(═O)(═NR¹⁵)R¹⁴,    —O-(1-4C-alkylene)-S—R¹⁴, —O-(1-4C-alkylene)-S(O)—R¹⁴,    —O-(1-4C-alkylene)-S(O)₂—R¹⁴, or —O-(1-4C-alkylene)-S(═O)(═NR¹⁵)    R¹⁴,    -   and    -   n is 1.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R⁴ is    -   (a) hydrogen,    -   (b) hydroxy,    -   (c) 1-6C-alkoxy optionally substituted with        -   (C1) 1 or 2 hydroxy,        -   (c2) —NR⁹R¹⁰,        -   (c3) —S—R¹⁴,        -   (c4) —S(O)—R¹⁴,        -   (c5) —S(O)₂—R¹⁴,        -   (c6) —S(═O)(═NR¹⁵)R¹⁴,        -   (c7) —S(O)₂NR⁹R¹⁰,    -   (d)

-   -    whereby the * is the point of attachment,    -   (e)

-   -    whereby the * is the point of attachment,    -   (f) cyano, or    -   (g) —S(O)₂-(1-4C-alkyl).

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R⁴ is    -   (a) hydrogen,    -   (b) hydroxy,    -   (c) 1-4C-alkoxy optionally substituted with        -   (c1) 1 or 2 hydroxy,        -   (c2) —NR⁹R¹⁰,        -   (c3) —S—R¹⁴,        -   (c4) —S(O)—R¹⁴,        -   (c5) —S(O)₂—R¹⁴,        -   (c6) —S(═O)(═NR¹⁵)R¹⁴,        -   (c7) —S(O)₂NR⁹R¹⁰,    -   (f) cyano, or    -   (g) —S(O)₂-(1-4C-alkyl).

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R⁴ is    -   (a) hydrogen,    -   (c) 1-4C-alkoxy optionally substituted with        -   (c1) hydroxy,        -   (c3) —S—R¹⁴,        -   (c4) —S(O)—R¹⁴,        -   (c5) —S(O)₂—R¹⁴,        -   (c6) —S(═O)(═NR¹⁵)R¹⁴, or        -   (c7) —S(O)₂NR⁹R¹⁰.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R⁴ is hydrogen.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R⁵ is    -   (a) hydrogen,    -   (b) 2-6C-hydroxyalkyl,    -   (c)

-   -    whereby the * is the point of attachment,    -   (d) —C(O)-(1-6C-alkyl),    -   (e) —C(O)-(1-6C-alkylene)-O-(1-6C-alkyl), or    -   (f) —C(O)-(1-6C-alkylene)-O-(1-6C-alkylene)-O-(1-6C-alkyl).

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R⁵ is hydrogen.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R⁶ is halogen, cyano, C(O)NR¹¹R¹², or C(O)OR¹³.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R⁶ is halogen or cyano.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R⁶ is C(O)NR¹¹R¹², or C(O)OR¹³.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R⁶ is C(O)OR¹³.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   m is 0, 1, or 2.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   m is 0, or 1.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   m is 1.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   m is 0.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R⁷ is hydrogen, halogen, cyano, 1-6C-alkyl, 2-6C-alkenyl,    1-6C-alkoxy, 1-6C-haloalkoxy, 3-6C-cycloalkyl, C(O)NR¹¹R¹² or    NR⁹R¹⁰.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R⁷ is hydrogen, halogen, cyano, 1-3C-alkyl, 2-3C-alkenyl,    1-3C-alkoxy, 1-3C-haloalkoxy, 3-6C-cycloalkyl, C(O)NR¹¹R¹² or    NR⁹R¹⁰.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R⁷ is 3-6C-cycloalkyl.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R⁷ is cyclopropyl.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R⁷ is hydrogen, halogen, cyano, 1-6C-alkyl, 2-6C-alkenyl,    1-6C-alkoxy, 1-6C-haloalkoxy, 3-6C-cycloalkyl.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R⁸ is hydrogen, halogen, cyano, 1-6C-alkyl, 2-6C-alkenyl,    1-6C-alkoxy, 1-6C-haloalkoxy, 3-6C-cycloalkyl or NR⁹R¹⁰.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R⁸ is hydrogen, halogen, cyano, 1-3C-alkyl, 2-3C-alkenyl,    1-3C-alkoxy, 1-3C-haloalkoxy, 3-6C-cycloalkyl or NR⁹R¹⁰.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R⁸ is 1-3C-alkyl.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R⁸ is methyl.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R⁸ is hydrogen, halogen, cyano, 1-3C-alkyl, 2-3C-alkenyl,    1-3C-alkoxy, 1-3C-haloalkoxy or 3-6C-cycloalkyl.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R⁷ and R⁸ form together with the two carbon atoms to which they are    attached a 6-membered aromatic ring, which is optionally substituted    independently one or more times with halogen or 1-3C-alkyl.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R⁷ and R⁸ form together with the two carbon atoms to which they are    attached a 6-membered aromatic ring.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R⁷ and R⁸ form together a n-propylene or a n-butylene group.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R⁹ is hydrogen or 1-6C-alkyl.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R⁹ is hydrogen or 1-3C-alkyl.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹⁰ is hydrogen or 1-6C-alkyl.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹⁰ is hydrogen or 1-3C-alkyl.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R⁹ and R¹⁰ together with the nitrogen atom to which they are    attached form a 4-6-membered heterocyclic ring optionally containing    one further heteroatom selected from the group consisting of 0, S or    N,

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R⁹ and R¹⁰ together with the nitrogen atom to which they are    attached form a morpholine ring.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹¹ is hydrogen, 1-6C-alkyl, 2-6C-hydroxyalkyl, or    (1-4C-alkyl)-S(O)₂-(1-4C-alkyl).

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹¹ is hydrogen, 1-3C-alkyl, or 2-3C-hydroxyalkyl.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹¹ is hydrogen, or 1-3C-alkyl.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹² is hydrogen, 1-6C-alkyl, 2-6C-hydroxyalkyl, or    (1-4C-alkyl)-S(O)₂-(1-4C-alkyl).

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹² is hydrogen, or 1-3C-alkyl.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹² is hydrogen, 1-3C-alkyl, or 2-3C-hydroxyalkyl.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹³ is hydrogen or 1-4C-alkyl.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹³ is hydrogen or 1-3C-alkyl.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹³ is hydrogen or ethyl.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹³ is hydrogen.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹³ is ethyl.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹⁴ is a group selected from 1-6C-alkyl, 3-7C-cycloalkyl, phenyl,    benzyl, wherein said group is optionally substituted with one or two    or three substituents, identically or differently, selected from the    group of hydroxy, halogen, or NR⁹R¹⁰.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹⁴ is a group selected from 1-3C-alkyl, and 3-7C-cycloalkyl.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹⁴ is 1-3C-alkyl.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹⁴ is methyl.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹⁵ is hydrogen, cyano, or C(O)R¹⁶.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹⁵ is hydrogen.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹⁶ is 1-6C-alkyl, or 1-6C-haloalkyl.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹⁶ is methyl, or trifluoromethyl.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹⁶ is methyl.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹⁶ is trifluoromethyl.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹⁷ is halogen, cyano, C(O)NR¹¹R¹², or C(O)OR¹³.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹⁷ is C(O)NR¹¹R¹², or C(O)OR¹³.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹⁷ is C(O)NR¹¹R¹².

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹⁷ is C(O)OR¹³.

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹⁸ is    -   (a) hydrogen,    -   (b) 1-6C-alkyl optionally substituted with        -   (b1) 1 or 2 hydroxy,        -   (b2) 1-6C-alkoxy,        -   (b3) —C(O)OR¹³,        -   (b4) —C(O)NR¹¹R¹²,        -   (b5) —NR⁹R¹⁰,        -   (b6) —S—R¹⁴,        -   (b7) —S(O)—R¹⁴,        -   (b8) —S(O)₂—R¹⁴,        -   (b9) —S(═O)(═NR¹⁵)R¹⁴,        -   (b10) —S(O)₂NR⁹R¹⁰,    -   (c) —S(O)₂-(1-4C-alkyl),    -   (d) —C(O)-(1-6C-alkyl).

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹⁸ is    -   (a) hydrogen,    -   (b) 1-4C-alkyl optionally substituted with        -   (b1) 1 or 2 hydroxy,        -   (b2) 1-3C-alkoxy,        -   (b3) —C(O)OR¹³,        -   (b4) —C(O)NR¹¹R¹²,        -   (b5) —NR⁹R¹⁰,        -   (b6) —S—R¹⁴,        -   (b7) —S(O)—R¹⁴,        -   (b8) —S(O)₂—R¹⁴,        -   (b9) —S(═O)(═NR¹⁵)R¹⁴,        -   (b10) —S(O)₂NR⁹R¹⁰,    -   (c) —S(O)₂-(1-4C-alkyl),    -   (d) —C(O)-(1-3C-alkyl).

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹⁸ is    -   (a) hydrogen,    -   (b) 1-4C-alkyl optionally substituted with        -   (b1) hydroxy,        -   (b2) 1-3C-alkoxy,        -   (b3) —C(O)OR¹³,        -   (b4) —C(O)NR¹¹R¹²,        -   (b5) —NR⁹R¹⁰,        -   (b6) —S—R¹⁴,        -   (b7) —S(O)—R¹⁴,        -   (b8) —S(O)₂—R¹⁴,        -   (b9) —S(═O)(═NR¹⁵)R¹⁴,    -   (d) —C(O)-(1-3C-alkyl).

Another aspect of the invention are compounds of formula (I), as definedsupra, in which

-   R¹⁸ is    -   (a) hydrogen,    -   (b) 1-2C-alkyl optionally substituted with        -   (b1) hydroxy,        -   (b2) methoxy,        -   (b3) —C(O)OR¹³,        -   (b5) —NR⁹R¹⁰,        -   (b8) —S(O)₂—R¹⁴,    -   (d) acetyl.

DEFINITIONS

Constituents which are optionally substituted as stated herein, may besubstituted, unless otherwise noted, one or more times, independentlyfrom one another at any possible position. When any variable occurs morethan one time in any constituent, each definition is independent. Forexample, when R³, R⁴, R⁶, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵ in and/or R¹⁷occur more than one time in any compound of formula (I) each definitionof R³, R⁴, R⁶, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁷ is independent.

Unless defined otherwise in the claims and in the description, theconstituents defined below can optionally be substituted, one or moretimes, identically or differently, with a substituent selected from:

hydroxy, halogen, cyano, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy,—NR⁹R¹⁰, cyano, (═O), —C(O)NR¹¹R¹², —C(O)OR¹³. An alkyl constituentbeing multiply substituted by halogen includes also a completelyhalogenated alkyl moiety such as e.g. CF₃.

Should a constituent be composed of more than one part, e.g.—O-(1-6C-alkyl)-(3-7C-cycloalkyl), the position of a possiblesubstituent can be at any of these parts at any suitable position. Ahyphen at the beginning or at the end of the constituent marks the pointof attachment to the rest of the molecule. Should a ring be substitutedthe substitutent could be at any suitable position of the ring, also ona ring nitrogen atom if suitable.

The term “comprising” when used in the specification includes“consisting of”.

If it is referred to “as mentioned above” or “mentioned above” withinthe description it is referred to any of the disclosures made within thespecification in any of the preceding pages.

“suitable” within the sense of the invention means chemically possibleto be made by methods within the knowledge of a skilled person.

“1-6C-alkyl” is a straight-chain or branched alkyl group having 1 to 6carbon atoms. Examples are methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl and tert-butyl, pentyl, hexyl, preferably 1-4carbon atoms (1-4C-alkyl), more preferably 1-3 carbon atoms(1-3C-alkyl). Other alkyl constituents mentioned herein having anothernumber of carbon atoms shall be defined as mentioned above taking intoaccount the different length of their chain. Those parts of constituentscontaining an alkyl chain as a bridging moiety between two other partsof the constituent which usually is called an “alkylene” moiety isdefined in line with the definition for alkyl above including thepreferred length of the chain e.g. methylene, ethylene, n-propylene,iso-propylene, n-butylene, isobutylene, tert-butylene.

“2-6C-alkenyl” is a straight chain or branched alkenyl radical having 2to 6 carbon atoms. Examples are the but-2-enyl, but-3-enyl (homoallyl),prop-1-enyl, prop-2-enyl (allyl) and the ethenyl (vinyl) radicals.

“Halogen” within the meaning of the present invention is iodine,bromine, chlorine or fluorine, preferably “halogen” within the meaningof the present invention is chlorine or fluorine.

“1-6C-haloalkyl” is a straight-chain or branched alkyl group having 1 to6 carbon atoms in which at least one hydrogen is substituted by ahalogen atom. Examples are chloromethyl or 2-bromoethyl. For a partiallyor completely fluorinated C1-C4-alkyl group, the following partially orcompletely fluorinated groups are considered, for example: fluoromethyl,difluoromethyl, trifluoromethyl, fluoroethyl, 1,1-difluoroethyl,1,2-difluoroethyl, 1,1,1-trifluoroethyl, tetrafluoroethyl, andpenta-fluoroethyl, whereby difluoromethyl, trifluoromethyl, or1,1,1-trifluoroethyl are preferred. All possible partially or completelyfluorinated 1-6C-alkyl groups are considered to be encompassed by theterm 1-6C-haloalkyl.

“1-6C-hydroxyalkyl” is a straight-chain or branched alkyl group having 1to 6 carbon atoms in which at least one hydrogen atom is substituted bya hydroxy group. Examples are hydroxymethyl, 1-hydroxyethyl,2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl,2,3-dihydroxypropyl, 3-hydroxy-2-methyl-propyl,2-hydroxy-2-methyl-propyl, 1-hydroxy-2-methyl-propyl.

“1-6C-alkoxy” represents radicals, which in addition to the oxygen atom,contain a straight-chain or branched alkyl radical having 1 to 6 carbonatoms. Examples which may be mentioned are the hexoxy, pentoxy, butoxy,isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy andmethoxy radicals, preferred are methoxy, ethoxy, propoxy, isopropoxy. Incase the alkoxy group may be substituted, substituents as defined(c1)-(c7) may be situated at any carbon atom of the alkoxy group beingchemically suitable.

“1-6C-haloalkoxy” represents radicals, which in addition to the oxygenatom, contain a straight-chain or branched alkyl radical having 1 to 6carbon atoms in which at least one hydrogen is substituted by a halogenatom. Examples are —O—CFH₂, —O—CF₂H, —O—CF₃, —O—CH₂—CFH₂, —O—CH₂—CF₂H,—O—CH₂—CF₃. Preferred are —O—CF₂H, —O—CF₃, —O—CH₂—CF₃.

“3-7C-cycloalkyl” stands for cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl, preferably cyclopropyl.

The NR⁹R¹⁰ group includes, for example, NH₂, N(H)CH₃, N(CH₃)₂,—N(H)CH₂CH₃ and —N(CH₃)CH₂CH₃.

The —C(O)NR¹¹R¹² group includes, for example, —C(O)NH₂, —C(O)N(H)CH₃,—C(O)N(CH₃)₂, —C(O)N(H)CH₂CH₃, —C(O)N(CH₃)CH₂CH₃ or —C(O)N(CH₂CH₃)₂. IfR¹¹ or R¹² are not hydrogen, they may be substituted by hydroxy.

The —C(O)OR¹³ group includes, for example, —C(O)OH, —C(O)OCH₃,—C(O)OC₂H₅, —C(O)OC₃H₇, —C(O)OCH(CH₃)₂, —C(O)OC₄H₉.

A “heterocyclic ring” represents a monocyclic, nonaromatic heterocyclicradical containing, 4 to 6 ring atoms, and 1 or 2 heteroatoms and/orhetero groups independently selected from the series consisting of N, O,S, SO, SO₂. The heterocyclyl radicals can be saturated or partiallyunsaturated and, unless stated otherwise, may be optionally substituted,one or more times, identically or differently, with a substituentselected from: 1-4C-alkyl, 1-4C-haloalkyl, 1-4C-alkoxy, hydroxy,fluorine or (═O) whereby the 1-4C-alkyl may be optionally furthersubstituted with hydroxy and the double bonded oxygen atom leads to acarbonyl group together with the carbon atom of the heterocyclyl ring atany suitable position. Particularly preferred heterocyclic radicals are4- to 6-membered monocyclic saturated heterocyclyl radicals having up totwo hetero atoms from the series consisting of O, N and S, morepreferred 5- to 6-membered heterocyclic radicals. The following may bementioned by way of example and by preference: pyrrolidinyl,3-hydroxypyrrolidinyl, piperidinyl, 3-hydroxypiperidinyl,4-hydroxypiperidinyl, 3-fluoropiperidinyl, 3,3-difluoropiperidinyl,4-fluoropiperidinyl, 4,4-difluoropiperidinyl, piperazinyl,N-methyl-piperazinyl, N-(2-hydroxyethyl)-piperazinyl, morpholinyl,thiomorpholinyl.

“6-membered aromatic ring” represents a phenyl ring.

In the context of the properties of the compounds of the presentinvention the term “pharmacokinetic profile” means one single parameteror a combination thereof including permeability, bioavailability,exposure, and pharmacodynamic parameters such as duration, or magnitudeof pharmacological effect, as measured in a suitable experiment.Compounds with improved pharmacokinetic profiles can, for example, beused in lower doses to achieve the same effect, may achieve a longerduration of action, or may achieve a combination of both effects.

Salts of the compounds according to the invention include all inorganicand organic acid addition salts and salts with bases, especially allpharmaceutically acceptable inorganic and organic acid addition saltsand salts with bases, particularly all pharmaceutically acceptableinorganic and organic acid addition salts and salts with basescustomarily used in pharmacy.

One aspect of the invention are salts of the compounds according to theinvention including all inorganic and organic acid addition salts,especially all pharmaceutically acceptable inorganic and organic acidaddition salts, particularly all pharmaceutically acceptable inorganicand organic acid addition salts customarily used in pharmacy. Anotheraspect of the invention are the salts with di- and tricarboxylic acids.

Examples of acid addition salts include, but are not limited to,hydrochlorides, hydrobromides, phosphates, nitrates, sulfates, salts ofsulfamic acid, formates, acetates, propionates, citrates, D-gluconates,benzoates, 2-(4-hydroxybenzoyl)-benzoates, butyrates, salicylates,sulfosalicylates, lactates, maleates, laurates, malates, fumarates,succinates, oxalates, malonates, pyruvates, acetoacetates, tartarates,stearates, benzensulfonates, toluenesulfonates, methanesulfonates,trifluoromethansulfonates, 3-hydroxy-2-naphthoates, benzenesulfonates,naphthalinedisulfonates and trifluoroacetates.

Examples of salts with bases include, but are not limited to, lithium,sodium, potassium, calcium, aluminum, magnesium, titanium, meglumine,ammonium, salts optionally derived from NH₃ or organic amines havingfrom 1 to 16 C-atoms such as e.g. ethylamine, diethylamine,triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine,dibenzylamine, N-methylmorpholine, arginine, lysine, ethylendiamine,N-methylpiperindine and guanidinium salts.

In the present text, in particular in the Experimental Section, for thesynthesis of intermediates and of examples of the present invention,when a compound is mentioned as a salt form with the corresponding baseor acid, the exact stoichiometric composition of said salt form, asobtained by the respective preparation and/or purification process, is,in most cases, unknown.

Unless specified otherwise, suffixes to chemical names or structuralformulae such as “hydrochloride”, “trifluoroacetate”, “sodium salt”, or“x HCl”, “x CF₃COOH”, “x Na⁺”, for example, are to be understood as nota stoichiometric specification, but solely as a salt form.

This applies analogously to cases in which synthesis intermediates orexample compounds or salts thereof have been obtained, by thepreparation and/or purification processes described, as solvates, suchas hydrates with (if defined) unknown stoichiometric composition.

The salts include water-insoluble and, particularly, water-solublesalts.

According to the person skilled in the art the compounds of formula (I)according to this invention as well as their salts may contain, e.g.when isolated in crystalline form, varying amounts of solvents. Includedwithin the scope of the invention are therefore all solvates and inparticular all hydrates of the compounds of formula (I) according tothis invention as well as all solvates and in particular all hydrates ofthe salts of the compounds of formula (I) according to this invention.

The term “combination” in the present invention is used as known topersons skilled in the art and may be present as a fixed combination, anon-fixed combination or kit-of-parts.

A “fixed combination” in the present invention is used as known topersons skilled in the art and is defined as a combination wherein thesaid first active ingredient and the said second active ingredient arepresent together in one unit dosage or in a single entity. One exampleof a “fixed combination” is a pharmaceutical composition wherein thesaid first active ingredient and the said second active ingredient arepresent in admixture for simultaneous administration, such as in aformulation. Another example of a “fixed combination” is apharmaceutical combination wherein the said first active ingredient andthe said second active ingredient are present in one unit without beingin admixture.

A non-fixed combination or “kit-of-parts” in the present invention isused as known to persons skilled in the art and is defined as acombination wherein the said first active ingredient and the said secondactive ingredient are present in more than one unit. One example of anon-fixed combination or kit-of-parts is a combination wherein the saidfirst active ingredient and the said second active ingredient arepresent separately. The components of the non-fixed combination orkit-of-parts may be administered separately, sequentially,simultaneously, concurrently or chronologically staggered.

Any such combination of a compound of formula (I) of the presentinvention with an anti-cancer agent as defined below is an embodiment ofthe invention.

The term “(chemotherapeutic) anti-cancer agents”, includes but is notlimited to 131I-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin,alemtuzumab, alitretinoin, altretamine, aminoglutethimide, amrubicin,amsacrine, anastrozole, arglabin, arsenic trioxide, asparaginase,azacitidine, basiliximab, belotecan, bendamustine, bevacizumab,bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin,busulfan, cabazitaxel, calcium folinate, calcium levofolinate,capecitabine, carboplatin, carmofur, carmustine, catumaxomab, celecoxib,celmoleukin, cetuximab, chlorambucil, chlormadinone, chlormethine,cisplatin, cladribine, clodronic acid, clofarabine, copanlisib,crisantaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine,dactinomycin, darbepoetin alfa, dasatinib, daunorubicin, decitabine,degarelix, denileukin diftitox, denosumab, deslorelin, dibrospidiumchloride, docetaxel, doxifluridine, doxorubicin, doxorubicin+estrone,eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin,enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa,epoetin beta, eptaplatin, eribulin, erlotinib, estradiol, estramustine,etoposide, everolimus, exemestane, fadrozole, filgrastim, fludarabine,fluorouracil, flutamide, formestane, fotemustine, fulvestrant, galliumnitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, glutoxim,goserelin, histamine dihydrochloride, histrelin, hydroxycarbamide, I-125seeds, ibandronic acid, ibritumomab tiuxetan, idarubicin, ifosfamide,imatinib, imiquimod, improsulfan, interferon alfa, interferon beta,interferon gamma, ipilimumab, irinotecan, ixabepilone, lanreotide,lapatinib, lenalidomide, lenograstim, lentinan, letrozole, leuprorelin,levamisole, lisuride, lobaplatin, lomustine, lonidamine, masoprocol,medroxyprogesterone, megestrol, melphalan, mepitiostane, mercaptopurine,methotrexate, methoxsalen, Methyl aminolevulinate, methyltestosterone,mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone,mitolactol, mitomycin, mitotane, mitoxantrone, nedaplatin, nelarabine,nilotinib, nilutamide, nimotuzumab, nimustine, nitracrine, ofatumumab,omeprazole, oprelvekin, oxaliplatin, p53 gene therapy, paclitaxel,palifermin, palladium-103 seed, pamidronic acid, panitumumab, pazopanib,pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta),pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine,pentostatin, peplomycin, perfosfamide, picibanil, pirarubicin,plerixafor, plicamycin, poliglusam, polyestradiol phosphate,polysaccharide-K, porfimer sodium, pralatrexate, prednimustine,procarbazine, quinagolide, radium-223 chloride, raloxifene, raltitrexed,ranimustine, razoxane, refametinib, regorafenib, risedronic acid,rituximab, romidepsin, romiplostim, roniciclib, sargramostim,sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sorafenib,streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen,tasonermin, teceleukin, tegafur, tegafur+gimeracil+oteracil, temoporfin,temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin,thalidomide, thiotepa, thymalfasin, tioguanine, tocilizumab, topotecan,toremifene, tositumomab, trabectedin, trastuzumab, treosulfan,tretinoin, trilostane, triptorelin, trofosfamide, tryptophan, ubenimex,valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine,vincristine, vindesine, vinflunine, vinorelbine, vorinostat, vorozole,yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer,zoledronic acid, zorubicin.

The compounds according to the invention and their salts can exist inthe form of tautomers which are included in the embodiments of theinvention. Tautomers, sometimes referred to as proton-shift tautomers,are two or more compounds that are related by the migration of ahydrogen atom accompanied by the switch of one or more single bonds andone or more adjacent double bonds. The compounds of this invention mayexist in one or more tautomeric forms.

The compounds of the invention may, depending on their structure, existin different stereoisomeric forms. These forms include configurationalisomers or optionally conformational isomers (enantiomers and/ordiastereoisomers including those of atropisomers). The present inventiontherefore includes enantiomers, diastereoisomers as well as mixturesthereof. From those mixtures of enantiomers and/or disastereoisomerspure stereoisomeric forms can be isolated with methods known in the art,preferably methods of chromatography, especially high pressure liquidchromatography (HPLC) using achiral or chiral phase. The inventionfurther includes all mixtures of the stereoisomers mentioned aboveindependent of the ratio, including the racemates.

Furthermore, the present invention includes all possible crystallineforms, polymorphs of the compounds of the present invention, either assingle polymorphs, or as a mixture of more than one polymorph, in anyratio.

Furthermore, derivatives of the compounds of formula (I) and the saltsthereof which are converted into a compound of formula (I) or a saltthereof in a biological system (bioprecursors or pro-drugs) are coveredby the invention. Said biological system is e.g. a mammalian organism,particularly a human subject. The bioprecursor is, for example,converted into the compound of formula (I) or a salt thereof bymetabolic processes.

The invention also includes all suitable isotopic variations of acompound of the invention. An isotopic variation of a compound of theinvention is defined as one in which at least one atom is replaced by anatom having the same atomic number but an atomic mass different from theatomic mass usually or predominantly found in nature. Examples ofisotopes that can be incorporated into a compound of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus,sulphur, fluorine, chlorine, bromine and iodine, such as ²H (deuterium),³H (tritium), ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³³P, ³³S, ³⁴S, ³⁵S,³⁶S, ¹⁸F, ³⁶Cl, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁹I and ¹³¹I, respectively. Certainisotopic variations of a compound of the invention, for example, thosein which one or more radioactive isotopes such as ³H or ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionstudies. Tritiated and carbon-14, i.e., ¹⁴C, isotopes are particularlypreferred for their ease of preparation and detectability. Further,substitution with isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements andhence may be preferred in some circumstances. Isotopic variations of acompound of the invention can generally be prepared by conventionalprocedures known by a person skilled in the art such as by theillustrative methods or by the preparations described in the exampleshereafter using appropriate isotopic variations of suitable reagents.

It has now been found, and this constitutes the basis of the presentinvention, that said compounds of the present invention have surprisingand advantageous properties.

In particular, said compounds of the present invention have surprisinglybeen found to effectively inhibit Bub1 kinase and may therefore be usedfor the treatment or prophylaxis of diseases of uncontrolled cellgrowth, proliferation and/or survival, inappropriate cellular immuneresponses, or inappropriate cellular inflammatory responses or diseaseswhich are accompanied with uncontrolled cell growth, proliferationand/or survival, inappropriate cellular immune responses, orinappropriate cellular inflammatory responses, particularly in which theuncontrolled cell growth, proliferation and/or survival, inappropriatecellular immune responses, or inappropriate cellular inflammatoryresponses is mediated by Bub1 kinase, such as, for example,haematological tumours, solid tumours, and/or metastases thereof, e.g.leukaemias and myelodysplastic syndrome, malignant lymphomas, head andneck tumours including brain tumours and brain metastases, tumours ofthe thorax including non-small cell and small cell lung tumours,gastrointestinal tumours, endocrine tumours, mammary and othergynaecological tumours, urological tumours including renal, bladder andprostate tumours, skin tumours, and sarcomas, and/or metastases thereof.

The intermediates used for the synthesis of the compounds of claims 1-5as described below, as well as their use for the synthesis of thecompounds of claims 1-5, are one further aspect of the presentinvention. Preferred intermediates are the Intermediate Examples asdisclosed below.

General Procedures

The compounds according to the invention can be prepared according tothe following schemes 1 through 12.

The schemes and procedures described below illustrate synthetic routesto the compounds of general formula (I) of the invention and are notintended to be limiting. It is obvious to the person skilled in the artthat the order of transformations as exemplified in the Schemes can bemodified in various ways. The order of transformations exemplified inthe Schemes is therefore not intended to be limiting. In addition,interconversion of any of the substituents, R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R¹⁷ or R¹⁸ can be achieved before and/or after the exemplifiedtransformations. These modifications can be such as the introduction ofprotecting groups, cleavage of protecting groups, reduction or oxidationof functional groups, halogenation, metalation, substitution or otherreactions known to the person skilled in the art. These transformationsinclude those which introduce a functionality which allows for furtherinterconversion of substituents. Appropriate protecting groups and theirintroduction and cleavage are well-known to the person skilled in theart (see for example T. W. Greene and P. G. M. Wuts in Protective Groupsin Organic Synthesis, 3rd edition, Wiley 1999). Specific examples aredescribed in the subsequent paragraphs.

One route for the preparation of compounds of general formula (Ia) isdescribed in Scheme 1a. In instances where this route is not feasible,Scheme 1 b can be applied.

Scheme 1a

Scheme 1a Route for the preparation of compounds of general formula(Ia), wherein R¹, R², R³, R⁶, R⁷, R⁸, R¹⁸, T, Y, m and n have themeaning as given for general formula (I), supra. In addition,interconversion of any of the substituents, R¹, R², R³, R⁶, R⁷, R⁸ orR¹⁸ can be achieved before and/or after the exemplified transformations.These modifications can be such as the introduction of protectinggroups, cleavage of protecting groups, reduction or oxidation offunctional groups, halogenation, metalation, substitution or otherreactions known to the person skilled in the art. These transformationsinclude those which introduce a functionality which allows for furtherinterconversion of substituents. Appropriate protecting groups and theirintroduction and cleavage are well-known to the person skilled in theart (see for example T. W. Greene and P. G. M. Wuts in Protective Groupsin Organic Synthesis, 3rd edition, Wiley 1999). Specific examples aredescribed in the subsequent paragraphs.

Compounds A, B, C, D, E, F and G are either commercially available orcan be prepared according to procedures available from the publicdomain, as understandable to the person skilled in the art. Specificexamples are described in the subsequent paragraphs. X represents F, Cl,Br, I, boronic acid or a boronic acid ester, such as for example4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane (boronic acid pinacoleester). X′ represents a leaving group such as for example a Cl, Br or I,or X′ stands for an aryl sulfonate such as for example p-toluenesulfonate, or for an alkyl sulfonate such as for example methanesulfonate or trifluoromethane sufonate.

Intermediates of general formula A can be converted to intermediates ofgeneral formula (1-7) by reaction with a suitable organometalliccompound, such as, for example bromo(ethyl)magnesium, in a suitablesolvent system, such as, for example, diethylether, at a temperaturebetween 0° C. and boiling point of the respective solvent, preferablythe reaction is carried out under reflux.

Intermediates of general formula (1-7) can be converted to intermediatesof general formula (1-6) by reaction with a suitable oxalate (C), suchas, for example diethyl oxalate, in the presence of a suitable base,such as, for example bis-(trimethylsilyl)lithiumamide, in a suitablesolvent system, such as, for example, diethylether, at a temperaturebetween −78° C. and room temperature, preferably the reaction is carriedout at room temperature.

Compounds of general formula (1-6) are converted to intermediates ofgeneral formula (1-5) by treatment with tert-butyl hydrazinecarboxylate(D), in a suitable solvent system, such as, for example, ethanol, in atemperature range from room temperature to the boiling point of therespective solvent, preferably the reaction is carried out at theboiling point of the respective solvent.

Compounds of general formula (1-5) are converted to intermediates ofgeneral formula (1-4) by reaction under acidic conditions, such as, forexample, by reaction with hydrochloric acid, in a suitable solventsystem, such as, for example, dioxane, in a temperature range from 0° C.to room temperature, preferably the reaction is carried out at roomtemperature.

Intermediates of general formula (1-4) can be reacted with a suitablysubstituted benzyl halide or benzyl sulfonate of general formula (E),such as, for example, a benzyl bromide, in a suitable solvent system,such as, for example, tetrahydrofuran, in the presence of a suitablebase, such as, for example, sodium hydride in a temperature range from0° C. to the boiling point of the respective solvent, preferably thereaction is carried out at room temperature, to furnish compounds ofgeneral formula (1-3).

Intermediates of general formula (1-3) can be converted intointermediates of general formula (1-2) by reacting with deprotonatedacetonitrile. Deprotonation of acetonitrile is carried out with asuitable base such as for example n-butyllithium in a suitable solventsystem, such as, for example, tetrahydrofuran, in a temperature rangefrom −78° C. to room temperature, preferably the reaction is carried at−78° C.

Intermediates of general formula (1-2) can be reacted with a suitablysubstituted hydrazine of general formula (F), such as, for examplemonomethylhydrazine, in a suitable solvent system, such as, for example,methanol, in a temperature range from room temperature to the boilingpoint of the respective solvent to furnish compounds of general formula(1-1).

Intermediates of general formula (1-1) can be reacted with a suitablehalogen-substituted heteroaryl compounds of the general formula (G),such as, for example 4-bromopyridine, in the presence of a suitablebase, such as, for example sodium 2-methylpropan-2-olate, and a suitablepalladium catalyst, such as for example(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one-palladium, in the presence of asuitable ligand, such as for example1′-binaphthalene-2,2′-diylbis-(diphenylphosphane), in a suitable solventsystem, such as, for example, N,N-dimethylformamide, in a temperaturerange from room temperature to the boiling point of the respectivesolvent, preferably the reaction is carried out at 100° C. to furnishcompounds of general formula (Ia). Alternatively the following palladiumcatalysts can be used:

allylpalladium chloride dimmer, dichlorobis(benzonitrile)palladium (II),palladium (II) acetate, palladium (II) chloride,tetrakis(triphenylphosphine)palladium (0),tris(dibenzylideneacetone)dipalladium (0) or the following ligands:racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, rac-BINAP,1,1′-bis(diphenyl-phosphino)ferrocene,bis(2-diphenylphosphinophenyl)ether, di-tert-butylmethyl-phosphoniumtetrafluoroborate, 2-(di-tert-butylphosphino)biphenyl,tri-tert-butyl-phosphonium tetrafluoroborate, tri-2-furylphosphine,tris(2,4-di-tert-butylphenyl)-phosphite, tri-o-tolylphosphine.

Scheme 1b

Scheme 1 b. Alternative route for the preparation of compounds ofgeneral formula (Ia), wherein R¹, R², R³, R⁶, R⁷, R⁸, R¹⁸, T, Y, m and nhave the meaning as given for general formula (Ia), supra. In addition,interconversion of any of the substituents, R¹, R², R³, R⁶, R⁷, R⁸ orR¹⁸ can be achieved before and/or after the exemplified transformations.These modifications can be such as the introduction of protectinggroups, cleavage of protecting groups, reduction or oxidation offunctional groups, halogenation, metalation, substitution or otherreactions known to the person skilled in the art. These transformationsinclude those which introduce a functionality which allows for furtherinterconversion of substituents. Appropriate protecting groups and theirintroduction and cleavage are well-known to the person skilled in theart (see for example T. W. Greene and P. G. M. Wuts in Protective Groupsin Organic Synthesis, 3rd edition, Wiley 1999). Specific examples aredescribed in the subsequent paragraphs.

Compounds F and G are either commercially available or can be preparedaccording to procedures available from the public domain, asunderstandable to the person skilled in the art. Specific examples aredescribed in the subsequent paragraphs. X represents F, Cl, Br, I,boronic acid or a boronic acid ester, such as for example4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane (boronic acid pinacoleester).

Intermediates of general formula (1-2) can be reacted with a suitablysubstituted hydrazine of general formula (F), such as, for example(2-methanesulfonylethyl)hydrazine hydrochloride, in a suitable solventsystem, such as, for example, acetic acid, in a temperature range fromroom temperature to the boiling point of the respective solvent tofurnish compounds of general formula (1-1a).

Intermediates of general formula (1-1a) can be converted intointermediates of the general formula (1-1) by reaction with a suitableacid, such as, for example, aqueous hydrogen chloride in a suitablesolvent such as, for example, methanol in a temperature range from roomtemperature to the boiling point of the respective solvent, preferablythe reaction is carried out at 60° C. to furnish compounds of generalformula (1-1).

Intermediates of general formula (Ia) can be reacted with a suitablehalogen-substituted heteroaryl of the general formula (G), such as, forexample 4-bromopyridine, in the presence of a suitable base, such as,for example sodium 2-methylpropan-2-olate, and a suitable palladiumcatalyst, such as for example(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one-palladium, in the presence of asuitable ligand, such as for example1′-binaphthalene-2,2′-diylbis(diphenylphosphane), in a suitable solventsystem, such as, for example, N,N-dimethylformamide, in a temperaturerange from room temperature to the boiling point of the respectivesolvent, preferably the reaction is carried out at 100° C. to furnishcompounds of general formula (Id). Alternatively the following palladiumcatalysts can be used: allylpalladium chloride dimmer,dichlorobis(benzonitrile)palladium (II), palladium (II) acetate,palladium (II) chloride, tetrakis(triphenylphosphine)palladium (0),tris(dibenzylideneacetone)dipalladium (0) or the following ligands:

racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, rac-BINAP,1,1′-bis(diphenyl-phosphino)ferrocene,bis(2-diphenylphosphinophenyl)ether, di-tert-butylmethyl-phosphoniumtetrafluoroborate, 2-(di-tert-butylphosphino)biphenyl,tri-tert-butyl-phosphonium tetrafluoroborate, tri-2-furylphosphine,tris(2,4-di-tert-butylphenyl)-phosphite, tri-o-tolylphosphine.Scheme 1c (if R⁷═NH₂ and N(Alkyl)₂)

Scheme 1c. Route for the preparation of compounds of general formula(1-5-2), (wherein R¹, R², R³, R⁸ and n have the meaning as given forgeneral formula (I), supra. R^(C) and R^(D) represent Alkyl-groups,especially 1-4C-alkyl whereby the alkyl residues may be same ordifferent.

Intermediates (1-5-1-2) can be prepared following the procedure depictedin Bioorg Med Chem Lett, 2001, 11/6, 781-784.

Intermediates of general formula (1-5-1-2) can be converted tointermediates of general formula (1-5-2) by reaction with a suitablealkylating agent, such as, for example, iodomethane, in the presence ofa suitable base, such as, for example, lithiumhydride, in a suitablesolvent system, such as, for example, N,N-dimethylformamide, at atemperature between 0° C. and the boiling point of the respectivesolvent, preferably the reaction is carried out at room temperature.

Alternatively, intermediates of general formula (1-5-1-2) can bealkylated by reductive amination conditions to intermediates of generalformula (1-5-2), such as, for example, formaldehyde, palladium oncharcoal and hydrogen in a suitable solvent system, such as, forexample, tetrahydrofuran, at a temperature between 0° C. and the boilingpoint of the respective solvent, preferably the reaction is carried outat room temperature.

Intermediates of general formulae (1-5-1-2) and (1-5-2) can be convertedto compounds of the general formula (I) by the methods depicted inSchemes 1a and 2.

Scheme 1d (if R⁷=hydroxy, alkoxy, alkenyl or cycloalkyl)

Scheme 1 d. Route for the preparation of compounds of general formulae(1-5-3), (1-5-3-1), (1-5-4) and (1-5-5), wherein R¹, R², R³, R⁸ and nhave the meaning as given for general formula (I), supra. ORB representsa leaving group, such as for example trifluoromethylsulfonate.

Compounds B-1 and B-2 are either commercially available or can beprepared according to procedures available from the public domain, asunderstandable to the person skilled in the art.

A suitably substituted Benzylhydrazine (B-1) can be reacted with asuitably substituted Oxalacetate (B-2) in a suitable solvent system,such as, for example, acetic acid and dioxane, at temperatures rangingfrom 0° C. to the boiling point of the respective solvent, preferablythe reaction is carried out at 90° C., to furnish1-benzyl-5-hydroxy-1H-pyrazole-3-carboxylate intermediates of generalformula (1-5-3). As side products methyl or ethyl ethers (1-5-3-1) canbe isolated.

Intermediates of general formula (1-5-3) can be converted tointermediates of general formula (1-5-4) by reaction with a suitablesulfonic acid derivative, such as, for example, triflic anhydride, inthe presence of a suitable base, such as, for example, pyridine, in asuitable solvent system, such as, for example, dichloromethane, at atemperature between 0° C. and the boiling point of the respectivesolvent, preferably the reaction is carried out at room temperature.

Intermediates of general formula (1-5-4) can be converted tointermediates of general formula (1-5-5), wherein R⁷ has the meaning ofalkenyl or cycloalkyl, by reaction with boronic acids or boronic acidpinacole esters, such as, for example cyclopropylboronic acid, in thepresence of a suitable base, such as, for example sodium carbonate, anda suitable palladium catalyst, such as for exampletetrakis(triphenylphosphine)palladium(0), in a suitable solvent system,such as, for example, 1,2-dimethoxyethan, in a temperature range fromroom temperature to the boiling point of the respective solvent,preferably the reaction is carried out at 75° C.

Compounds, wherein R⁷ has the meaning of alkoxy and haloalkoyx can beobtained from hydroxy-compounds of general formula (1-5-3) byconventional procedures, such as by reaction with a suitable alkylatingagent, such as, for example, iodomethane, in the presence of a suitablebase, such as, for example, potassium carbonate, in a suitable solventsystem, such as, for example, acetone, at a temperature between 0° C.and the boiling point of the respective solvent, preferably the reactionis carried out at room temperature.

These compounds as well as Intermediates of general formulae (1-5-3),(1-5-4) and (1-5-5) can be converted to compounds of the general formula(I) by the methods depicted in schemes 1a and 2.

Scheme 1e (if R⁷=hydrogen, alkyl or cycloalkyl, and R⁸=halogen)

Scheme 1e. Route for the preparation of compounds of general formula(1-5-6), wherein R¹, R², R³, and n have the meaning as given for generalformula (I), supra. R⁷ has the meaning of hydrogen, alkyl or cycloalkyland R⁸ has the meaning of fluoro, chloro or bromo.

Compounds E are either commercially available or can be preparedaccording to procedures available from the public domain, asunderstandable to the person skilled in the art. Specific examples aredescribed in the subsequent paragraphs. X′ represents a leaving groupsuch as for example a Cl, Br or I, or X′ stands for an aryl sulfonatesuch as for example p-toluene sulfonate, or for an alkyl sulfonate suchas for example methane sulfonate or trifluoromethane sufonate.

Compounds of formula H are commercially available or described in theliterature (e.g. CAS-Reg.-No.: 1291177-21-3, 1281872-47-6, 1232838-31-1,1005584-90-6, 681034-80-0).

Compounds of formula H can be converted to Intermediates of the generalformula (1-5-6) by the method depicted in Scheme 1a.

Intermediates of general formula (1-5-6), can be converted to compoundsof the general formula (I) by the methods depicted in Schemes 1a and 2.

Scheme 1f (if R⁸═NO₂, NH₂ or N(Alkyl)₂)

Scheme 1f. Route for the preparation of compounds of general formula(1-5-10), wherein R¹, R², R³, R⁷ and n have the meaning as given forgeneral formula (I), supra. R^(C) and R^(D) represent Alkyl-groups,especially 1-4C-alkyl whereby the alkyl residues may be same ordifferent.

Compounds P and E are either commercially available or can be preparedaccording to procedures available from the public domain, asunderstandable to the person skilled in the art. Specific examples aredescribed in the subsequent paragraphs. X′ represents a leaving groupsuch as for example a Cl, Br or I, or X′ stands for an aryl sulfonatesuch as for example p-toluene sulfonate, or for an alkyl sulfonate suchas for example methane sulfonate or trifluoromethane sufonate.

A suitably substituted pyrazole with a carboxylic acid function (P) canbe esterificated with a suitably methylating or ethylation reagent, suchas, for example (trimethylsilyl)diazomethane, in a suitable solventsystem, such as, for example, tetrahydrofuran and methanol, attemperatures ranging from 0° C. to the boiling point of the respectivesolvent, preferably the reaction is carried out at 0° C., to furnishintermediates of general formula (1-5-7).

Intermediates of general formula (1-5-7) can be reacted with a suitablysubstituted benzyl halide or benzyl sulfonate of general formula (E),such as, for example, a benzyl bromide, in a suitable solvent system,such as, for example, tetrahydrofuran, in the presence of a suitablebase, such as, for example, sodium hydride in a temperature range fromroom temperature to the boiling point of the respective solvent,preferably the reaction is carried out at room temperature, to furnishcompounds of general formula (1-5-8).

Intermediates of general formula (1-5-8) can be converted tointermediates of general formula (1-5-9) by reaction with a suitablereduction agent, such as, for example, raney nickel and hydrazinehydrate, in a suitable solvent system, such as, for example, methanol,at a temperature between 0° C. and the boiling point of the respectivesolvent, preferably the reaction is carried out at room temperature.

Intermediates of general formula (1-5-9) can be converted tointermediates of general formula (1-5-10) by reaction with a suitablealkylating agent, such as, for example, iodomethane, in the presence ofa suitable base, such as, for example, lithiumhydride, in a suitablesolvent system, such as, for example, N,N-dimethylformamide, at atemperature between 0° C. and the boiling point of the respectivesolvent, preferably the reaction is carried out at room temperature.

Alternatively, intermediates of general formula (1-5-9) can be alkylatedby reductive amination conditions to intermediates of general formula(1-5-10), such as, for example, formaldehyde, palladium on charcoal andhydrogen, in a suitable solvent system, such as, for example,tetrahydrofuran, at a temperature between 0° C. and the boiling point ofthe respective solvent, preferably the reaction is carried out at roomtemperature.

Intermediates of general formulae (1-5-10) can be converted to compoundsof the general formula (I) by the methods depicted in Schemes 1a and 2.

Compounds of general formula (Ib) can be synthesised according to theprocedure depicted in Scheme 2.

Scheme 2

Scheme 2. Route for the preparation of compounds of general formula(Ib), wherein R¹, R², R³, R⁶, R⁷, R⁸, R¹⁸, T, Y, T m and n have themeaning as given for general formula (I), supra. In addition,interconversion of any of the substituents, R¹, R², R³, R⁶, R⁷, R⁸ andR¹⁸, can be achieved before and/or after the exemplifiedtransformations. These modifications can be such as the introduction ofprotecting groups, cleavage of protecting groups, reduction or oxidationof functional groups, halogenation, metalation, substitution or otherreactions known to the person skilled in the art. These transformationsinclude those which introduce a functionality which allows for furtherinterconversion of substituents. Appropriate protecting groups and theirintroduction and cleavage are well-known to the person skilled in theart (see for example T. W. Greene and P. G. M. Wuts in Protective Groupsin Organic Synthesis, 3rd edition, Wiley 1999). Further specificexamples are described in the subsequent paragraphs.

Compounds E, G, H, and Q are either commercially available or can beprepared according to procedures available from the public domain, asunderstandable to the person skilled in the art. Specific examples aredescribed in the subsequent paragraphs. X represents F, Cl, Br, I,boronic acid or a boronic acid ester, such as for example4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane (boronic acid pinacoleester). X′ and X″ represent leaving groups such as for example a Cl, Bror I, or X′ and X″ stand for an aryl sulfonate such as for examplep-toluene sulfonate, or for an alkyl sulfonate such as for examplemethane sulfonate or trifluoromethane sufonate.

Intermediates of general formula (1-4) can be reacted with a suitablysubstituted benzyl halide or benzyl sulfonate of general formula (E),such as, for example, a benzyl bromide, in a suitable solvent system,such as, for example, tetrahydrofuran, in the presence of a suitablebase, such as, for example, sodium hydride in a temperature range from0° C. to the boiling point of the respective solvent, preferably thereaction is carried out at room temperature, to furnish compounds ofgeneral formula (1-3).

Intermediates of general formula (1-3) can be reacted withaminoguanidine in a suitable solvent system, such as, for example,methanol, in a temperature range from room temperature to the boilingpoint of the respective solvent, to furnish compounds of general formula(1-9).

Intermediates of general formula (1-9) can be reacted with a suitablealkylating agent of general formula (Q), such as, for example,2-bromoethyl methyl ether, in the presence of a suitable base, such as,for example, potassium carbonate, in a suitable solvent system, such as,for example, N,N-dimethylformamide, at a temperature between 0° C. andthe boiling point of the respective solvent, preferably the reaction iscarried out at 60° C. to furnish compounds of general formula (1-8).

Intermediates of general formula (1-8) can be reacted with a suitablehalogen-substituted heteroaryl compounds of the general formula (G),such as, for example 4-bromopyridine, in the presence of a suitablebase, such as, for example sodium 2-methylpropan-2-olate, and a suitablepalladium catalyst, such as for example(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one-palladium, in the presence of asuitable ligand, such as for example1′-binaphthalene-2,2′-diylbis-(diphenylphosphane), in a suitable solventsystem, such as, for example, N,N-dimethylformamide, in a temperaturerange from room temperature to the boiling point of the respectivesolvent, preferably the reaction is carried out at 105° C. to furnishcompounds of general formula (Ib). Alternatively the following palladiumcatalysts can be used:

allylpalladium chloride dimmer, dichlorobis(benzonitrile)palladium (II),palladium (II) acetate, palladium (II) chloride,tetrakis(triphenylphosphine)palladium (0),tris(dibenzylideneacetone)dipalladium (0) or the following ligands:racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, rac-BINAP,1,1′-bis(diphenyl-phosphino)ferrocene,bis(2-diphenylphosphinophenyl)ether, di-tert-butylmethyl-phosphoniumtetrafluoroborate, 2-(di-tert-butylphosphino)biphenyl,tri-tert-butyl-phosphonium tetrafluoroborate, tri-2-furylphosphine,tris(2,4-di-tert-butylphenyl)-phosphite, tri-o-tolylphosphine.

Compounds of general formula (Ic) can be synthesised according to theprocedure depicted in Scheme 3.

Scheme 3

Scheme 3. Route for the preparation of compounds of general formula (I),wherein R¹, R², R³, R⁶, R¹⁸, T, Y, T m and n have the meaning as givenfor general formula (I), supra. In addition, interconversion of any ofthe substituents, R¹, R², R³, R⁶ and R¹⁸ can be achieved before and/orafter the exemplified transformations. These modifications can be suchas the introduction of protecting groups, cleavage of protecting groups,reduction or oxidation of functional groups, halogenation, metalation,substitution or other reactions known to the person skilled in the art.These transformations include those which introduce a functionalitywhich allows for further interconversion of substituents. Appropriateprotecting groups and their introduction and cleavage are well-known tothe person skilled in the art (see for example T. W. Greene and P. G. M.Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley1999). Further specific examples are described in the subsequentparagraphs.

Compounds E, Q and G are either commercially available or can beprepared according to procedures available from the public domain, asunderstandable to the person skilled in the art. Specific examples aredescribed in the subsequent paragraphs. X represents F, Cl, Br, I,boronic acid or a boronic acid ester, such as for example4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane (boronic acid pinacoleester). X′ and X″ represent leaving groups such as for example a Cl, Bror I, or X′ and X″ stand for an aryl sulfonate such as for examplep-toluene sulfonate, or for an alkyl sulfonate such as for examplemethane sulfonate or trifluoromethane sufonate.

Compound J (CAS Registry Number: 43120-28-1) can be reacted with asuitably substituted benzyl halide or benzyl sulfonate of generalformula (E), such as, for example, a benzyl bromide, in a suitablesolvent system, such as, for example, tetrahydrofuran, in the presenceof a suitable base, such as, for example, sodium hydride in atemperature range from 0° C. to the boiling point of the respectivesolvent, preferably the reaction is carried out at room temperature, tofurnish compounds of general formula (1-13).

Intermediates of general formula (1-13) can be reacted with compound H,aminoguanidine, in a suitable solvent system, such as, for example,methanol, in a temperature range from room temperature to the boilingpoint of the respective solvent, to furnish compounds of general formula(1-12).

Intermediates of general formula (1-12) can be reacted with a suitablealkylating agent of general formula (Q), such as, for example,2-bromoethyl methyl ether, in the presence of a suitable base, such as,for example, potassium carbonate, in a suitable solvent system, such as,for example, N,N-dimethylformamide, at a temperature between 0° C. andthe boiling point of the respective solvent, preferably the reaction iscarried out at 60° C. to furnish compounds of general formula (1-11).

Intermediates of general formula (1-11) can be reacted with a suitablehalogen-substituted heteroaryl compounds of the general formula (G),such as, for example 4-bromopyridine, in the presence of a suitablebase, such as, for example sodium 2-methylpropan-2-olate, and a suitablepalladium catalyst, such as for example(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one-palladium, in the presence of asuitable ligand, such as for example1′-binaphthalene-2,2′-diylbis-(diphenylphosphane), in a suitable solventsystem, such as, for example, N,N-dimethylformamide, in a temperaturerange from room temperature to the boiling point of the respectivesolvent, preferably the reaction is carried out at 105° C. to furnishcompounds of general formula (Ic). Alternatively the following palladiumcatalysts can be used:

allylpalladium chloride dimmer, dichlorobis(benzonitrile)palladium (II),palladium (II) acetate, palladium (II) chloride,tetrakis(triphenylphosphine)palladium (0),tris(dibenzylideneacetone)dipalladium (0) or the following ligands:racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, rac-BINAP,1,1′-bis(diphenyl-phosphino)ferrocene,bis(2-diphenylphosphinophenyl)ether, di-tert-butylmethyl-phosphoniumtetrafluoroborate, 2-(di-tert-butylphosphino)biphenyl,tri-tert-butyl-phosphonium tetrafluoroborate, tri-2-furylphosphine,tris(2,4-di-tert-butylphenyl)-phosphite, tri-o-tolylphosphine.

Compounds of general formula (Id) can be synthesised from compounds ofgeneral formula E and K, according to the procedure depicted in Scheme4.

Scheme 4

Scheme 4. Route for the preparation of compounds of general formula (I),wherein R¹, R², R³, R⁶, T, Y, m and n have the meaning as given forgeneral formula (I), supra. In addition, interconversion of any of thesubstituents, R¹, R², R³, R⁴, R⁶ can be achieved before and/or after theexemplified transformations. These modifications can be such as theintroduction of protecting groups, cleavage of protecting groups,reduction or oxidation of functional groups, halogenation, metalation,substitution or other reactions known to the person skilled in the art.These transformations include those which introduce a functionalitywhich allows for further interconversion of substituents. Appropriateprotecting groups and their introduction and cleavage are well-known tothe person skilled in the art (see for example T. W. Greene and P. G. M.Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley1999). Further specific examples are described in the subsequentparagraphs.

Compounds E and G are either commercially available or can be preparedaccording to procedures available from the public domain, asunderstandable to the person skilled in the art. Specific examples aredescribed in the subsequent paragraphs. X represents F, Cl, Br, I,boronic acid or a boronic acid ester, such as for example4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane (boronic acid pinacoleester). X′ represents a leaving group such as for example a Cl, Br or I,or X′ stands for an aryl sulfonate such as for example p-toluenesulfonate, or for an alkyl sulfonate such as for example methanesulfonate or trifluoromethane sufonate.

Compound K (CAS Registry Number: 66607-27-0) can be reacted with asuitably substituted benzyl halide or benzyl sulfonate of generalformula (E), such as, for example, a benzyl bromide, in a suitablesolvent system, such as, for example, tetrahydrofuran, in the presenceof a suitable base, such as, for example, cesium carbonate, in atemperature range from 0° C. to the boiling point of the respectivesolvent, preferably the reaction is carried out at room temperature, tofurnish compounds of general formula (1-14).

Intermediates of general formula (1-14) can be reacted with compound L,4-nitro-1H-pyrazole (CAS Registry Number: 2075-46-9), in a suitablesolvent system, such as, for example, N,N-dimethylformamide, in thepresence of a suitable base, such as, for example, cesium carbonate, andin the presence of copper (II) oxide and iron (III) acetyl acetonate, ina temperature range from room temperature to the boiling point of therespective solvent, preferably the reaction is carried out at 90° C., tofurnish compounds of general formula (1-15).

Intermediates of general formula (1-15) can be reduced to thecorresponding amino compounds, for example by reaction with raney nickeland hydrazine, in a suitable solvent system, such as, for example,methanol, in a temperature range from room temperature to the boilingpoint of the respective solvent, preferably the reaction is carried outat room temperature, to furnish compounds of general formula (1-16).

Intermediates of general formula (1-16) can be reacted with a suitablehalogen-substituted heteroaryl compounds of the general formula (G),such as, for example 4-bromopyridine, in the presence of a suitablebase, such as, for example sodium 2-methylpropan-2-olate, and a suitablepalladium catalyst, such as for example(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one-palladium, in the presence of asuitable ligand, such as for example1′-binaphthalene-2,2′-diylbis-(diphenylphosphane), in a suitable solventsystem, such as, for example, N,N-dimethylformamide, in a temperaturerange from room temperature to the boiling point of the respectivesolvent, preferably the reaction is carried out at 105° C. to furnishcompounds of general formula (Id). Alternatively the following palladiumcatalysts can be used:

allylpalladium chloride dimmer, dichlorobis(benzonitrile)palladium (II),palladium (II) acetate, palladium (II) chloride,tetrakis(triphenylphosphine)palladium (0),tris(dibenzylideneacetone)dipalladium (0) or the following ligands:racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, rac-BINAP,1,1′-bis(diphenyl-phosphino)ferrocene,bis(2-diphenylphosphinophenyl)ether, di-tert-butylmethyl-phosphoniumtetrafluoroborate, 2-(di-tert-butylphosphino)biphenyl,tri-tert-butyl-phosphonium tetrafluoroborate, tri-2-furylphosphine,tris(2,4-di-tert-butylphenyl)-phosphite, tri-o-tolylphosphine.

Compounds of general formula (Ie) can be synthesised according to theprocedure depicted in Scheme 5.

Scheme 5

Scheme 5. Route for the preparation of compounds of general formula (I),wherein R¹, R², R³, R⁶ T, Y, m and n have the meaning as given forgeneral formula (I), supra. In addition, interconversion of any of thesubstituents, R¹, R², R³, R⁶ can be achieved before and/or after theexemplified transformations. These modifications can be such as theintroduction of protecting groups, cleavage of protecting groups,reduction or oxidation of functional groups, halogenation, metalation,substitution or other reactions known to the person skilled in the art.These transformations include those which introduce a functionalitywhich allows for further interconversion of substituents. Appropriateprotecting groups and their introduction and cleavage are well-known tothe person skilled in the art (see for example T. W. Greene and P. G. M.Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley1999). Further specific examples are described in the subsequentparagraphs.

Compounds E and G are either commercially available or can be preparedaccording to procedures available from the public domain, asunderstandable to the person skilled in the art. Specific examples aredescribed in the subsequent paragraphs. X represents F, Cl, Br, I,boronic acid or a boronic acid ester, such as for example4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane (boronic acid pinacoleester). X′ represents a leaving group such as for example a Cl, Br or I,or X′ stands for an aryl sulfonate such as for example p-toluenesulfonate, or for an alkyl sulfonate such as for example methanesulfonate or trifluoromethane sufonate.

Compound M (CAS Registry Number: 50264-88-5) can be reacted with asuitably substituted benzyl halide or benzyl sulfonate of generalformula (E), such as, for example, a benzyl bromide, in a suitablesolvent system, such as, for example, tetrahydrofuran, in the presenceof a suitable base, such as, for example, cesium carbonate, in atemperature range from 0° C. to the boiling point of the respectivesolvent, preferably the reaction is carried out at room temperature, tofurnish compounds of general formula (1-19).

Intermediates of general formula (1-19) can be converted tointermediates of general formula (1-18) by reaction with a suitablealcoholate, such as, for example sodium methanolate, in a suitablesolvent system, such as, for example, the corresponding alcohol, e.g.methanol, at a temperature between room temperature and the boilingpoint of the respective solvent, preferably the reaction is carried outat room temperature, and subsequent treatment with a suitable source ofammonium, such as for example, ammonium chloride in the presence of asuitable acid, such as for example acetic acid in a temperature rangefrom room temperature to the boiling point of the respective solvent,preferably the reaction is carried out at 50° C.

Intermediates of general formula (1-18) can be reacted with potassiumthiocyanate in a suitable solvent system, such as, for example,methanol, in a temperature range from 0° C. to 50° C., preferably thereaction is carried out in a temperature range from 0° C. to roomtemperature, to furnish compounds of general formula (1-17).

Intermediates of general formula (1-17) can be reacted with a suitablehalogen-substituted heteroaryl compounds of the general formula (G),such as, for example 4-bromopyridine, in the presence of a suitablebase, such as, for example sodium 2-methylpropan-2-olate, and a suitablepalladium catalyst, such as for example(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one-palladium, in the presence of asuitable ligand, such as for example1′-binaphthalene-2,2′-diylbis-(diphenylphosphane), in a suitable solventsystem, such as, for example, N,N-dimethylformamide, in a temperaturerange from room temperature to the boiling point of the respectivesolvent, preferably the reaction is carried out at 105° C. to furnishcompounds of general formula (Ie). Alternatively the following palladiumcatalysts can be used:

allylpalladium chloride dimmer, dichlorobis(benzonitrile)palladium (II),palladium (II) acetate, palladium (II) chloride,tetrakis(triphenylphosphine)palladium (0),tris(dibenzylideneacetone)dipalladium (0) or the following ligands:racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, rac-BINAP,1,1′-bis(diphenyl-phosphino)ferrocene,bis(2-diphenylphosphinophenyl)ether, di-tert-butylmethyl-phosphoniumtetrafluoroborate, 2-(di-tert-butylphosphino)biphenyl,tri-tert-butyl-phosphonium tetrafluoroborate, tri-2-furylphosphine,tris(2,4-di-tert-butylphenyl)-phosphite, tri-o-tolylphosphine.

Compounds of general formula (Ia-1) can be converted into compounds ofgeneral formulae (If), (Ig) and (Ih) according to the procedure depictedin Scheme 6.

Scheme 6

Scheme 6. Process for the preparation of compounds of general formulae(If), (Ig) and (Ih), wherein R¹, R², R³, R⁶, R⁷, R⁸, R¹⁴, T, Y, m and nhave the meaning as given for general formula (I), supra. p representsan integer from 1 to 6. In addition, interconversion of any of thesubstituents, R¹, R², R³, R⁷ and R⁸ can be achieved before and/or afterthe exemplified transformations. These modifications can be such as theintroduction of protecting groups, cleavage of protecting groups,reduction or oxidation of functional groups, halogenation, metalation,substitution or other reactions known to the person skilled in the art.These transformations include those which introduce a functionalitywhich allows for further interconversion of substituents. Appropriateprotecting groups and their introduction and cleavage are well-known tothe person skilled in the art (see for example T. W. Greene and P. G. M.Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley1999). Specific examples are described in the subsequent paragraphs.

Compounds of general formula (N) are either commercially available orcan be prepared according to procedures available from the publicdomain, as understandable to the person skilled in the art. X′represents F, Cl, Br, I or a sulfonate, e.g. trifluoromethylsulfonate orp-toluolsulfonate.

Compounds of general formula (Ia-1) can be reacted with a suitablehalo-alkyl-alkyl-sulfide of the general formula (N), such as, forexample 3-chloropropyl methyl sulfide, in the presence of a suitablebase, such as, for example potassium carbonate, in a suitable solventsystem, such as, for example, N,N-dimethylformamide, in a temperaturerange from room temperature to the boiling point of the respectivesolvent, preferably the reaction is carried out at 60° C. to furnishcompounds of general formula (If).

Compounds of general formula (If) are converted to compounds of generalformula (Ig) by treatment with a suitable oxidation agent, such as forexample meta-chloroperbenzoic acid, in a suitable solvent, such as, forexample, chloroform, in a temperature range from 0° C. to the boilingpoint of the respective solvent, preferably the reaction is carried outat 0° C.

Compounds of general formula (Ig) can be converted into compounds ofgeneral formula (Ih) by treatment with a suitable oxidation agent, suchas for example hydrogen peroxide and the reagent diethylazodicarboxylate, in a suitable solvent, such as, for example,tetrahydrofuran, in a temperature range from 0° C. to the boiling pointof the respective solvent, preferably the reaction is carried out at 50°C.

Compounds of general formula (Ib-1) can be converted into compounds ofgeneral formulae (Ij), (Ik) and (Im) according to the procedure depictedin Scheme 7.

Scheme 7

Scheme 7. Process for the preparation of compounds of general formulae(Ij), (Ik) and (Im), wherein R¹, R², R³, R⁶, R⁷, R⁸, R¹⁴, T, Y, m and nhave the meaning as given for general formula (I), supra. p representsan integer from 1 to 6. X′ represents F, Cl, Br, I or a sulfonate, e.g.trifluoromethylsulfonate or p-toluolsulfonate.

Compounds of general formula (Ib-1) can be transformed to compounds ofthe general formula (Ij) in analogy to the method described in Scheme 6.Compounds of general formula (Ij) can be transformed to compounds of thegeneral formula (Ik) in analogy to the method described in Scheme 6.Compounds of general formula (Ik) can be transformed to compounds of thegeneral formula (Im) in analogy to the method described in Scheme 6.

Compounds of general formulae (In) and (Io) can be synthesized fromcompounds of general formula (Ig) according to the procedure depicted inScheme 8.

Scheme 8

Scheme 8 Route for the preparation of compounds of general formulae(In), and (Io), wherein R¹, R², R³, R⁶, R⁷, R⁸, R⁹, R¹⁴, R¹⁵, T, Y, mand n have the meaning as given for general formula (I), supra, and p isan integer from 1 to 6. In addition, interconversion of any of thesubstituents, R¹, R², R³, R⁶, R⁷, R⁸, R⁹, and R¹⁵ can be achieved beforeand/or after the exemplified transformations. These modifications can besuch as the introduction of protecting groups, cleavage of protectinggroups, reduction or oxidation of functional groups, halogenation,metalation, substitution or other reactions known to the person skilledin the art. These transformations include those which introduce afunctionality which allows for further interconversion of substituents.Appropriate protecting groups and their introduction and cleavage arewell-known to the person skilled in the art (see for example T. W.Greene and P. G. M. Wuts in Protective Groups in Organic Synthesis, 3rdedition, Wiley 1999). Specific examples are described in the subsequentparagraphs.

Intermediates of general formula (Ig) can be reacted to the protectedsulfoximine with a suitable reagent mixture, such as, for example2,2,2-trifluoro acetamide, iodo-benzene diacetate and magnesium oxide,with a suitable catalyst, such as, for example, rhodium(II) acetatedimer, in a suitable solvent system, such as, for example,dichloromethane, in a temperature range from 0° C. to the boiling pointof the respective solvent, preferably the reaction is carried out atroom temperature to furnish the protected compounds. Deprotection can beaccomplished under suitable conditions, such as, for example in the caseof trifluoroacetate, a suitable base, such as, for example, potassiumcarbonate, in a suitable solvent system, such as, for example, methanol,in a temperature range from 0° C. to the boiling point of the respectivesolvent, preferably the reaction is carried out at room temperature tofurnish the compounds of general formula (10). The sulfoximines ofgeneral formula (10) can be N-functionalized by several methods tofurnish sulfoximines of general formula (In).

For the preparation of N-functionalized sulfoximines multiple methodsare known:

-   Alkylation: see for example: a) U. Lücking et al, US    2007/0232632; b) C. R. Johnson, J. Org. Chem. 1993, 58, 1922; c) C.    Bolm et al, Synthesis 2009, 10, 1601.-   Acylation: see for example: a) C. Bolm et al, Chem. Europ. J. 2004,    10, 2942; b) C. Bolm et al, Synthesis 2002, 7, 879; c) C. Bolm et    al, Chem. Europ. J. 2001, 7, 1118.-   Arylation: see for example: a) C. Bolm et al, Tet. Lett. 1998, 39,    5731; b) C. Bolm et al., J. Org. Chem. 2000, 65, 169; c) C. Bolm et    al, Synthesis 2000, 7, 911; d) C. Bolm et al, J. Org. Chem. 2005,    70, 2346; e) U. Lücking et al, WO2007/71455.-   Reaction with isocyanates: see for example: a) V. J. Bauer et al, J.    Org. Chem. 1966, 31, 3440; b) C. R. Johnson et al, J. Am. Chem. Soc.    1970, 92, 6594; c) S. Allenmark et al, Acta Chem. Scand. Ser. B    1983, 325; d) U. Lücking et al, US2007/0191393.-   Reaction with sulfonylchlorides: see for example: a) D. J. Cram et    al, J. Am. Chem. Soc. 1970, 92, 7369; b) C. R. Johnson et al, J.    Org. Chem. 1978, 43, 4136; c) A. C. Barnes, J. Med. Chem. 1979, 22,    418; d) D. Craig et al, Tet. 1995, 51, 6071; e) U. Lücking et al,    US2007/191393.-   Reaction with chloroformiates: see for example: a) P. B. Kirby et    al, DE2129678; b) D. J. Cram et al, J. Am. Chem. Soc. 1974, 96,    2183; c) P. Stoss et al, Chem. Ber. 1978, 111, 1453; d) U. Lücking    et al, WO2005/37800.

Compounds of general formulae (Ip) and (Iq) can be synthesized fromcompounds of general formula (Ig) according to the procedure depicted inScheme 9.

Scheme 9

Scheme 9. Route for the preparation of compounds of general formulae(Ip), and (Iq), wherein R¹, R², R³, R⁶, R⁷, R⁸, R⁹, R¹⁴, R¹⁵, T, Y, T mand n have the meaning as given for general formula (I), supra, and p isan integer from 1 to 6.

Compounds of general formula (Ik) can be transformed to compounds of thegeneral formulae (Ip) and (Iq) in analogy to the method described inScheme 8. The sulfoximines of general formula (Iq) can beN-functionalized by several methods to furnish sulfoximines of generalformula (In).

For the preparation of N-functionalized sulfoximines multiple methodsare known:

-   Alkylation: see for example: a) U. Lücking et al, US    2007/0232632; b) C. R. Johnson, J. Org. Chem. 1993, 58, 1922; c) C.    Bolm et al, Synthesis 2009, 10, 1601.-   Acylation: see for example: a) C. Bolm et al, Chem. Europ. J. 2004,    10, 2942; b) C. Bolm et al, Synthesis 2002, 7, 879; c) C. Bolm et    al, Chem. Europ. J. 2001, 7, 1118.-   Arylation: see for example: a) C. Bolm et al, Tet. Lett. 1998, 39,    5731; b) C. Bolm et al., J. Org. Chem. 2000, 65, 169; c) C. Bolm et    al, Synthesis 2000, 7, 911; d) C. Bolm et al, J. Org. Chem. 2005,    70, 2346; e) U. Lücking et al, WO2007/71455.-   Reaction with isocyanates: see for example: a) V. J. Bauer et al, J.    Org. Chem. 1966, 31, 3440; b) C. R. Johnson et al, J. Am. Chem. Soc.    1970, 92, 6594; c) S. Allenmark et al, Acta Chem. Scand. Ser. B    1983, 325; d) U. Lücking et al, US2007/0191393.-   Reaction with sulfonylchlorides: see for example: a) D. J. Cram et    al, J. Am. Chem. Soc. 1970, 92, 7369; b) C. R. Johnson et al, J.    Org. Chem. 1978, 43, 4136; c) A. C. Barnes, J. Med. Chem. 1979, 22,    418; d) D. Craig et al, Tet. 1995, 51, 6071; e) U. Lücking et al,    US2007/191393.-   Reaction with chloroformiates: see for example: a) P. B. Kirby et    al, DE2129678; b) D. J. Cram et al, J. Am. Chem. Soc. 1974, 96,    2183; c) P. Stoss et al, Chem. Ber. 1978, 111, 1453; d) U. Lücking    et al, WO2005/37800.

Intermediates of general formula (1-33) can be synthesized fromcompounds of general formula (Ir) which are compounds of formula (I)wherein R³=methoxy or ethoxy, via debenzylation according to theprocedure depicted in Scheme 10.

Scheme 10

Scheme 10. Route for the preparation of compounds of general formula(1-33), wherein the group A and the substituents R¹, R², R⁷ and R⁸ havethe meaning as given for general formula (I), supra.

Compounds of general formula (Ir) are converted to intermediates ofgeneral formula (1-33) by treatment with a suitable acid system, suchas, for example a mixture of trifluoroacetic acid andtrifluoromethanesulfonic acid, in a suitable solvent, such as, forexample, dichloroethan, in a temperature range from room temperature tothe boiling point of the respective solvent, preferably the reaction iscarried out at room temperature.

Compounds of general formulae (Is), (It), (Iu) can be synthesized fromcompounds of general formulae (1-31) and (1-33) according to theprocedure depicted in Scheme 11.

Scheme 11

Scheme 11. Route for the preparation of compounds of general formulae(Is), (It) and (Iu), wherein the group A and the substituents R¹, R²,R⁷, R⁸, R¹⁴, R¹⁵ and m have the meaning as given for general formula(I), supra, and p represents an integer from 1 to 6. In addition,interconversion of any of the group A and the substituents R¹, R², R⁷,R⁸ and R¹⁵ can be achieved before and/or after the exemplifiedtransformations. These modifications can be such as the introduction ofprotecting groups, cleavage of protecting groups, reduction or oxidationof functional groups, halogenation, metalation, substitution or otherreactions known to the person skilled in the art. These transformationsinclude those which introduce a functionality which allows for furtherinterconversion of substituents. Appropriate protecting groups and theirintroduction and cleavage are well-known to the person skilled in theart (see for example T. W. Greene and P. G. M. Wuts in Protective Groupsin Organic Synthesis, 3rd edition, Wiley 1999). Specific examples aredescribed in the subsequent paragraphs.

Compounds of general formula (N) are either commercially available orcan be prepared according to procedures available from the publicdomain, as understandable to the person skilled in the art. X′represents F, Cl, Br, I or a sulfonate, e.g. trifluoromethylsulfonate orp-toluolsulfonate.

Intermediates of general formula (1-30) can be reacted with a suitablehalo-alkyl-alkyl-sulfide of the general formula (N), such as, forexample 3-chloropropyl methyl sulfide, in the presence of a suitablebase, such as, for example potassium carbonate, in a suitable solventsystem, such as, for example, N,N-dimethylformamide, in a temperaturerange from room temperature to the boiling point of the respectivesolvent, preferably the reaction is carried out at 60° C. to furnishcompounds of general formula (1-31).

Intermediates of general formula (1-31) can be transformed intointermediates of the general formula (1-32), where X′ represents aleaving group, by reaction for example with a suitable halogenationreagent, such as, for example, hydrogen bromide, in a suitable solventsystem, such as, for example, diethylether, in a temperature range fromroom temperature to the boiling point of the respective solvent,preferably the reaction is carried out at room temperature to furnishthe intermediate of general formula (1-32).

Intermediates of general formula (1-33) can be reacted with a suitablysubstituted benzyl halide or benzyl sulfonate of general formula (1-32),such as, for example, a benzyl bromide, in a suitable solvent system,such as, for example, tetrahydrofuran, in the presence of a suitablebase, such as, for example, sodium hydride in a temperature range fromroom temperature to the boiling point of the respective solvent,preferably the reaction is carried out at room temperature, to furnishcompounds of general formula (Is).

Compounds of general formula (Is) can be oxidized with a suitableoxidation agent, such as, for example meta-chloroperbenzoic acid, in asuitable solvent system, such as, for example, chloroform, in atemperature range from 0° C. to the boiling point of the respectivesolvent, preferably the reaction is carried out at 0° C. to furnishcompounds of general formula (It).

Compounds of general formula (It) can be converted into compounds ofgeneral formula (Iu) by treatment with a suitable oxidation agent, suchas for example hydrogen peroxide and the reagent diethylazodicarboxylate, in a suitable solvent, such as, for example,tetrahydrofuran, in a temperature range from 0° C. to the boiling pointof the respective solvent, preferably the reaction is carried out at 50°C.

Compounds of general formulae (Iv) and (Iw) can be synthesized fromcompounds of general formulae (It) according to the procedure depictedin Scheme 12.

Scheme 12

Scheme 12. Route for the preparation of compounds of general formulae(Iv) and (Iw), wherein the group A and the substituents R¹, R², R⁷, R⁸,R¹⁴, R¹⁵ and m have the meaning as given for general formula (I), supra,and p represents an integer from 1 to 6. In addition, interconversion ofany of the group A and the substituents R¹, R², R⁷, R⁸ and R¹⁵ can beachieved before and/or after the exemplified transformations. Thesemodifications can be such as the introduction of protecting groups,cleavage of protecting groups, reduction or oxidation of functionalgroups, halogenation, metalation, substitution or other reactions knownto the person skilled in the art. These transformations include thosewhich introduce a functionality which allows for further interconversionof substituents. Appropriate protecting groups and their introductionand cleavage are well-known to the person skilled in the art (see forexample T. W. Greene and P. G. M. Wuts in Protective Groups in OrganicSynthesis, 3rd edition, Wiley 1999). Specific examples are described inthe subsequent paragraphs.

Compounds of general formula (It) can be reacted to the protectedsulfoximine with a suitable reagent mixture, such as, for example2,2,2-trifluoro acetamide, iodo-benzene diacetate and magnesium oxide,with a suitable catalyst, such as, for example, rhodium(II) acetatedimer, in a suitable solvent system, such as, for example,dichloromethane, in a temperature range from 0° C. to the boiling pointof the respective solvent, preferably the reaction is carried out atroom temperature to furnish the protected compounds. Deprotection can beaccomplished under suitable conditions, such as, for example in the caseof trifluoroacetate, a suitable base, such as, for example, potassiumcarbonate, in a suitable solvent system, such as, for example, methanol,in a temperature range from 0° C. to the boiling point of the respectivesolvent, preferably the reaction is carried out at room temperature offurnish the compounds of general formula (Iw). The sulfoximines ofgeneral formula (Iw) can be N-functionalized by several methods tofurnish sulfoximines of general formula (Iv).

For the preparation of N-functionalized sulfoximines multiple methodsare known:

-   Alkylation: see for example: a) U. Lücking et al, US    2007/0232632; b) C. R. Johnson, J. Org. Chem. 1993, 58, 1922; c) C.    Bolm et al, Synthesis 2009, 10, 1601-   Acylation: see for example: a) C. Bolm et al, Chem. Europ. J. 2004,    10, 2942; b) C. Bolm et al, Synthesis 2002, 7, 879; c) C. Bolm et    al, Chem. Europ. J. 2001, 7, 1118.-   Arylation: see for example: a) C. Bolm et al, Tet. Lett. 1998, 39,    5731; b) C. Bolm et al., J. Org. Chem. 2000, 65, 169; c) C. Bolm et    al, Synthesis 2000, 7, 911; d) C. Bolm et al, J. Org. Chem. 2005,    70, 2346; e) U. Lücking et al, WO2007/71455.-   Reaction with isocyanates: see for example: a) V. J. Bauer et al, J.    Org. Chem. 1966, 31, 3440; b) C. R. Johnson et al, J. Am. Chem. Soc.    1970, 92, 6594; c) S. Allenmark et al, Acta Chem. Scand. Ser. B    1983, 325; d) U. Lücking et al, US2007/0191393.-   Reaction with sulfonylchlorides: see for example: a) D. J. Cram et    al, J. Am. Chem. Soc. 1970, 92, 7369; b) C. R. Johnson et al, J.    Org. Chem. 1978, 43, 4136; c) A. C. Barnes, J. Med. Chem. 1979, 22,    418; d) D. Craig et al, Tet. 1995, 51, 6071; e) U. Lücking et al,    US2007/191393.-   Reaction with chloroformiates: see for example: a) P. B. Kirby et    al, DE2129678; b) D. J. Cram et al, J. Am. Chem. Soc. 1974, 96,    2183; c) P. Stoss et al, Chem. Ber. 1978, 111, 1453; d) U. Lücking    et al, WO2005/37800.

One preferred aspect of the invention is the process for the preparationof the compounds of claims 1-5 according to the Examples.

It is known to the person skilled in the art that, if there are a numberof reactive centers on a starting or intermediate compound, it may benecessary to block one or more reactive centers temporarily byprotective groups in order to allow a reaction to proceed specificallyat the desired reaction center. A detailed description for the use of alarge number of proven protective groups is found, for example, in T. W.Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, 1999,3rd Ed., or in P. Kocienski, Protecting Groups, Thieme MedicalPublishers, 2000.

The compounds according to the invention are isolated and purified in amanner known per se, e.g. by distilling off the solvent in vacuo andrecrystallizing the residue obtained from a suitable solvent orsubjecting it to one of the customary purification methods, such aschromatography on a suitable support material. Furthermore, reversephase preparative HPLC of compounds of the present invention whichpossess a sufficiently basic or acidic functionality, may result in theformation of a salt, such as, in the case of a compound of the presentinvention which is sufficiently basic, a trifluoroacetate or formatesalt for example, or, in the case of a compound of the present inventionwhich is sufficiently acidic, an ammonium salt for example. Salts ofthis type can either be transformed into its free base or free acidform, respectively, by various methods known to the person skilled inthe art, or be used as salts in subsequent biological assays.Additionally, the drying process during the isolation of compounds ofthe present invention may not fully remove traces of cosolvents,especially such as formic acid or trifluoroacetic acid, to give solvatesor inclusion complexes. The person skilled in the art will recognisewhich solvates or inclusion complexes are acceptable to be used insubsequent biological assays. It is to be understood that the specificform (e.g. salt, free base, solvate, inclusion complex) of a compound ofthe present invention as isolated as described herein is not necessarilythe only form in which said compound can be applied to a biologicalassay in order to quantify the specific biological activity.

Salts of the compounds of formula (I) according to the invention can beobtained by dissolving the free compound in a suitable solvent (forexample a ketone such as acetone, methylethylketone ormethylisobutylketone, an ether such as diethyl ether, tetrahydrofuran ordioxane, a chlorinated hydrocarbon such as methylene chloride orchloroform, or a low molecular weight aliphatic alcohol such asmethanol, ethanol or isopropanol) which contains the desired acid orbase, or to which the desired acid or base is then added. The acid orbase can be employed in salt preparation, depending on whether a mono-or polybasic acid or base is concerned and depending on which salt isdesired, in an equimolar quantitative ratio or one differing therefrom.The salts are obtained by filtering, reprecipitating, precipitating witha non-solvent for the salt or by evaporating the solvent. Salts obtainedcan be converted into the free compounds which, in turn, can beconverted into salts. In this manner, pharmaceutically unacceptablesalts, which can be obtained, for example, as process products in themanufacturing on an industrial scale, can be converted intopharmaceutically acceptable salts by processes known to the personskilled in the art. Especially preferred are hydrochlorides and theprocess used in the examples section.

Pure diastereomers and pure enantiomers of the compounds and saltsaccording to the invention can be obtained e.g. by asymmetric synthesis,by using chiral starting compounds in synthesis and by splitting upenantiomeric and diasteriomeric mixtures obtained in synthesis.

Enantiomeric and diastereomeric mixtures can be split up into the pureenantiomers and pure diastereomers by methods known to a person skilledin the art. Preferably, diastereomeric mixtures are separated bycrystallization, in particular fractional crystallization, orchromatography. Enantiomeric mixtures can be separated e.g. by formingdiastereomers with a chiral auxiliary agent, resolving the diastereomersobtained and removing the chiral auxiliary agent. As chiral auxiliaryagents, for example, chiral acids can be used to separate enantiomericbases such as e.g. mandelic acid and chiral bases can be used toseparate enantiomeric acids via formation of diastereomeric salts.Furthermore, diastereomeric derivatives such as diastereomeric esterscan be formed from enantiomeric mixtures of alcohols or enantiomericmixtures of acids, respectively, using chiral acids or chiral alcohols,respectively, as chiral auxiliary agents. Additionally, diastereomericcomplexes or diastereomeric clathrates may be used for separatingenantiomeric mixtures. Alternatively, enantiomeric mixtures can be splitup using chiral separating columns in chromatography. Another suitablemethod for the isolation of enantiomers is the enzymatic separation.

One preferred aspect of the invention is the process for the preparationof the compounds of claims 1 to 5 according to the examples.

Optionally, compounds of the formula (I) can be converted into theirsalts, or, optionally, salts of the compounds of the formula (I) can beconverted into the free compounds. Corresponding processes are customaryfor the skilled person.

Optionally, compounds of the formula (I) can be converted into theirN-oxides. The N-oxide may also be introduced by way of an intermediate.N-oxides may be prepared by treating an appropriate precursor with anoxidizing agent, such as meta-chloroperbenzoic acid, in an appropriatesolvent, such as dichloromethane, at suitable temperatures, such as from0° C. to 40° C., whereby room temperature is generally preferred.Further corresponding processes for forming N-oxides are customary forthe skilled person.

Commercial Utility

As mentioned supra, the compounds of the present invention havesurprisingly been found to effectively inhibit Bub1 finally resulting inapoptosis and cell death and may therefore be used for the treatment orprophylaxis of diseases of uncontrolled cell growth, proliferationand/or survival, inappropriate cellular immune responses, orinappropriate cellular inflammatory responses, or diseases which areaccompanied with uncontrolled cell growth, proliferation and/orsurvival, inappropriate cellular immune responses, or inappropriatecellular inflammatory responses, particularly in which the uncontrolledcell growth, proliferation and/or survival, inappropriate cellularimmune responses, or inappropriate cellular inflammatory responses ismediated by Bub1, such as, for example, benign and malignant neoplasia,more specifically haematological tumours, solid tumours, and/ormetastases thereof, e.g. leukaemias and myelodysplastic syndrome,malignant lymphomas, head and neck tumours including brain tumours andbrain metastases, tumours of the thorax including non-small cell andsmall cell lung tumours, gastrointestinal tumours, endocrine tumours,mammary and other gynaecological tumours, urological tumours includingrenal, bladder and prostate tumours, skin tumours, and sarcomas, and/ormetastases thereof,

especially haematological tumours, solid tumours, and/or metastases ofbreast, bladder, bone, brain, central and peripheral nervous system,cervix, colon, anum, endocrine glands (e.g. thyroid and adrenal cortex),endocrine tumours, endometrium, esophagus, gastrointestinal tumours,germ cells, kidney, liver, lung, larynx and hypopharynx, mesothelioma,ovary, pancreas, prostate, rectum, renal, small intestine, soft tissue,stomach, skin, testis, ureter, vagina and vulva as well as malignantneoplasias including primary tumors in said organs and correspondingsecondary tumors in distant organs (“tumor metastases”). Haematologicaltumors can e.g be exemplified by aggressive and indolent forms ofleukemia and lymphoma, namely non-Hodgkins disease, chronic and acutemyeloid leukemia (CML/AML), acute lymphoblastic leukemia (ALL), Hodgkinsdisease, multiple myeloma and T-cell lymphoma. Also included aremyelodysplastic syndrome, plasma cell neoplasia, paraneoplasticsyndromes, and cancers of unknown primary site as well as AIDS relatedmalignancies.

One aspect of the invention is the use of the compounds according toformula (I) for the treatment of cervical cancer, breast cancer, ovariancancer, non-small cell lung cancer (NSCLC), prostate cancer, coloncancer, pancreas cancer, osteo sacroma, acute myelogenous leucemia,Burkitt lymphoma, multiple myeloma, melanoma.

One aspect of the invention is the use of the compounds according toformula (I) for the treatment of cervical cancer, non-small cell lungcancer (NSCLC), prostate cancer, colon cancer, melanoma, particularlycervical cancer.

Another aspect of the invention is the use of the compounds according toformula (I) for the treatment of cervical cancer, NSCLC, prostatecancer, colon cancer and melanoma, particularly cervical cancer as wellas a method of treatment of cervical cancer, NSCLC, prostate cancer,colon cancer and melanoma, particularly cervical cancer, comprisingadministering an effective amount of a compound of formula (I). Anotheraspect of the invention is the use of the compounds according to formula(I) for the treatment of cervical cancer as well as a method oftreatment of cervical cancer comprising administering an effectiveamount of a compound of formula (I).

In accordance with an aspect of the present invention therefore theinvention relates to a compound of general formula I, or an N-oxide, asalt, a tautomer or a stereoisomer of said compound, or a salt of saidN-oxide, tautomer or stereoisomer particularly a pharmaceuticallyacceptable salt thereof, or a mixture of same, as described and definedherein, for use in the treatment or prophylaxis of a disease, especiallyfor use in the treatment of a disease.

Another particular aspect of the present invention is therefore the useof a compound of general formula I, described supra, or a stereoisomer,a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof,particularly a pharmaceutically acceptable salt thereof, or a mixture ofsame, for the prophylaxis or treatment of hyperproliferative disordersor disorders responsive to induction of cell death, e.g. apoptosis,especially for the treatment of a hyperproliferative disorder or adisorder responsive to induction of cell death, e.g. apoptosis.

The term “inappropriate” within the context of the present invention, inparticular in the context of “inappropriate cellular immune responses,or inappropriate cellular inflammatory responses”, as used herein, is tobe understood as preferably meaning a response which is less than, orgreater than normal, and which is associated with, responsible for, orresults in, the pathology of said diseases.

Preferably, the use is in the treatment or prophylaxis of diseases,especially the treatment, wherein the diseases are haematologicaltumours, solid tumours and/or metastases thereof.

Another aspect of the present invention is the use of a compound offormula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, asolvate, or a salt thereof, particularly a pharmaceutically acceptablesalt thereof, or a mixture of same, as described herein, in themanufacture of a medicament for the treatment or prophylaxis of adisease, wherein such disease is a hyperproliferative disorder or adisorder responsive to induction of cell death e.g. apoptosis. In anembodiment the disease is a haematological tumour, a solid tumour and/ormetastases thereof. In another embodiment the disease is cervical-,breast-, non-small cell lung-, prostate-, colon- and melanoma tumorand/or metastases thereof, in a preferred aspect the disease is cervicaltumor.

Method of Treating Hyper-Proliferative Disorders

The present invention relates to a method for using the compounds of thepresent invention and compositions thereof, to treat mammalianhyper-proliferative disorders. Compounds can be utilized to inhibit,block, reduce, decrease, etc., cell proliferation and/or cell division,and/or produce cell death e.g. apoptosis. This method comprisesadministering to a mammal in need thereof, including a human, an amountof a compound of this invention, or a pharmaceutically acceptable salt,isomer, polymorph, metabolite, hydrate, solvate or ester thereof; etc.which is effective to treat the disorder. Hyper-proliferative disordersinclude but are not limited, e.g., psoriasis, keloids, and otherhyperplasias affecting the skin, benign prostate hyperplasia (BPH),solid tumours, such as cancers of the breast, respiratory tract, brain,reproductive organs, digestive tract, urinary tract, eye, liver, skin,head and neck, thyroid, parathyroid and their distant metastases. Thosedisorders also include lymphomas, sarcomas, and leukaemias.

Examples of breast cancer include, but are not limited to invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to brain stem andhypophtalmic glioma, cerebellar and cerebral astrocytoma,medulloblastoma, ependymoma, as well as neuroectodermal and pinealtumour.

Tumours of the male reproductive organs include, but are not limited toprostate and testicular cancer. Tumours of the female reproductiveorgans include, but are not limited to endometrial, cervical, ovarian,vaginal, and vulvar cancer, as well as sarcoma of the uterus.

Tumours of the digestive tract include, but are not limited to anal,colon, colorectal, oesophageal, gallbladder, gastric, pancreatic,rectal, small-intestine, and salivary gland cancers.

Tumours of the urinary tract include, but are not limited to bladder,penile, kidney, renal pelvis, ureter, urethral and human papillary renalcancers.

Eye cancers include, but are not limited to intraocular melanoma andretinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellularcarcinoma (liver cell carcinomas with or without fibrolamellar variant),cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixedhepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, andnon-melanoma skin cancer.

Head-and-neck cancers include, but are not limited to laryngeal,hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oralcavity cancer and squamous cell. Lymphomas include, but are not limitedto AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-celllymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of thecentral nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue,osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma.

Leukemias include, but are not limited to acute myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, and hairy cell leukemia.

These disorders have been well characterized in humans, but also existwith a similar etiology in other mammals, and can be treated byadministering pharmaceutical compositions of the present invention.

The term “treating” or “treatment” as stated throughout this document isused conventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving thecondition of, etc., of a disease or disorder, such as a carcinoma.

Methods of Treating Kinase Disorders

The present invention also provides methods for the treatment ofdisorders associated with aberrant mitogen extracellular kinaseactivity, including, but not limited to stroke, heart failure,hepatomegaly, cardiomegaly, diabetes, Alzheimer's disease, cysticfibrosis, symptoms of xenograft rejections, septic shock or asthma.

Effective amounts of compounds of the present invention can be used totreat such disorders, including those diseases (e.g., cancer) mentionedin the Background section above. Nonetheless, such cancers and otherdiseases can be treated with compounds of the present invention,regardless of the mechanism of action and/or the relationship betweenthe kinase and the disorder.

The phrase “aberrant kinase activity” or “aberrant tyrosine kinaseactivity,” includes any abnormal expression or activity of the geneencoding the kinase or of the polypeptide it encodes. Examples of suchaberrant activity, include, but are not limited to, over-expression ofthe gene or polypeptide; gene amplification; mutations which produceconstitutively-active or hyperactive kinase activity; gene mutations,deletions, substitutions, additions, etc.

The present invention also provides for methods of inhibiting a kinaseactivity, especially of mitogen extracellular kinase, comprisingadministering an effective amount of a compound of the presentinvention, including salts, polymorphs, metabolites, hydrates, solvates,prodrugs (e.g.: esters) thereof, and diastereoisomeric forms thereof.Kinase activity can be inhibited in cells (e.g., in vitro), or in thecells of a mammalian subject, especially a human patient in need oftreatment.

Methods of Treating Angiogenic Disorders

The present invention also provides methods of treating disorders anddiseases associated with excessive and/or abnormal angiogenesis.

Inappropriate and ectopic expression of angiogenesis can be deleteriousto an organism. A number of pathological conditions are associated withthe growth of extraneous blood vessels. These include, e.g., diabeticretinopathy, ischemic retinal-vein occlusion, and retinopathy ofprematurity [Aiello et al. New Engl. J. Med. 1994, 331, 1480; Peer etal. Lab. Invest. 1995, 72, 638], age-related macular degeneration [AMD;see, Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855],neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma,inflammation, rheumatoid arthritis (RA), restenosis, in-stentrestenosis, vascular graft restenosis, etc. In addition, the increasedblood supply associated with cancerous and neoplastic tissue, encouragesgrowth, leading to rapid tumour enlargement and metastasis. Moreover,the growth of new blood and lymph vessels in a tumour provides an escaperoute for renegade cells, encouraging metastasis and the consequencespread of the cancer. Thus, compounds of the present invention can beutilized to treat and/or prevent any of the aforementioned angiogenesisdisorders, e.g., by inhibiting and/or reducing blood vessel formation;by inhibiting, blocking, reducing, decreasing, etc. endothelial cellproliferation or other types involved in angiogenesis, as well ascausing cell death, e.g. apoptosis, of such cell types.

In one aspect, the diseases of said method are haematological tumours,solid tumour and/or metastases thereof. In another aspect the diseasesof said method are cervical cancer, NSCLC, prostate cancer, colon cancerand melanoma, particularly cervical cancer.

The compounds of the present invention can be used in particular intherapy and prevention i.e. prophylaxis, especially in therapy of tumourgrowth and metastases, especially in solid tumours of all indicationsand stages with or without pre-treatment of the tumour growth.

Pharmaceutical Compositions of the Compounds of the Invention

This invention also relates to pharmaceutical compositions containingone or more compounds of the present invention. These compositions canbe utilised to achieve the desired pharmacological effect byadministration to a patient in need thereof. A patient, for the purposeof this invention, is a mammal, including a human, in need of treatmentfor the particular condition or disease.

Therefore, the present invention includes pharmaceutical compositionsthat are comprised of a pharmaceutically acceptable carrier or auxiliaryand a pharmaceutically effective amount of a compound, or salt thereof,of the present invention.

Another aspect of the invention is a pharmaceutical compositioncomprising a pharmaceutically effective amount of a compound of formula(I) and a pharmaceutically acceptable auxiliary for the treatment of adisease mentioned supra, especially for the treatment of haematologicaltumours, solid tumours and/or metastases thereof.

A pharmaceutically acceptable carrier or auxiliary is preferably acarrier that is non-toxic and innocuous to a patient at concentrationsconsistent with effective activity of the active ingredient so that anyside effects ascribable to the carrier do not vitiate the beneficialeffects of the active ingredient. Carriers and auxiliaries are all kindsof additives assisting to the composition to be suitable foradministration.

A pharmaceutically effective amount of compound is preferably thatamount which produces a result or exerts the intended influence on theparticular condition being treated.

The compounds of the present invention can be administered withpharmaceutically-acceptable carriers or auxiliaries well known in theart using any effective conventional dosage unit forms, includingimmediate, slow and timed release preparations, orally, parenterally,topically, nasally, ophthalmically, optically, sublingually, rectally,vaginally, and the like.

For oral administration, the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, troches, lozenges,melts, powders, solutions, suspensions, or emulsions, and may beprepared according to methods known to the art for the manufacture ofpharmaceutical compositions. The solid unit dosage forms can be acapsule that can be of the ordinary hard- or soft-shelled gelatine typecontaining auxiliaries, for example, surfactants, lubricants, and inertfillers such as lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of this invention may be tabletedwith conventional tablet bases such as lactose, sucrose and cornstarchin combination with binders such as acacia, corn starch or gelatine,disintegrating agents intended to assist the break-up and dissolution ofthe tablet following administration such as potato starch, alginic acid,corn starch, and guar gum, gum tragacanth, acacia, lubricants intendedto improve the flow of tablet granulation and to prevent the adhesion oftablet material to the surfaces of the tablet dies and punches, forexample talc, stearic acid, or magnesium, calcium or zinc stearate,dyes, colouring agents, and flavouring agents such as peppermint, oil ofwintergreen, or cherry flavouring, intended to enhance the aestheticqualities of the tablets and make them more acceptable to the patient.Suitable excipients for use in oral liquid dosage forms includedicalcium phosphate and diluents such as water and alcohols, forexample, ethanol, benzyl alcohol, and polyethylene alcohols, either withor without the addition of a pharmaceutically acceptable surfactant,suspending agent or emulsifying agent. Various other materials may bepresent as coatings or to otherwise modify the physical form of thedosage unit. For instance tablets, pills or capsules may be coated withshellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of anaqueous suspension. They provide the active ingredient in admixture witha dispersing or wetting agent, a suspending agent and one or morepreservatives. Suitable dispersing or wetting agents and suspendingagents are exemplified by those already mentioned above. Additionalexcipients, for example those sweetening, flavouring and colouringagents described above, may also be present.

The pharmaceutical compositions of this invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oilsuch as liquid paraffin or a mixture of vegetable oils. Suitableemulsifying agents may be (1) naturally occurring gums such as gumacacia and gum tragacanth, (2) naturally occurring phosphatides such assoy bean and lecithin, (3) esters or partial esters derived from fattyacids and hexitol anhydrides, for example, sorbitan monooleate, (4)condensation products of said partial esters with ethylene oxide, forexample, polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening and flavouring agents.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil such as, for example, arachis oil, olive oil, sesameoil or coconut oil, or in a mineral oil such as liquid paraffin. Theoily suspensions may contain a thickening agent such as, for example,beeswax, hard paraffin, or cetyl alcohol. The suspensions may alsocontain one or more preservatives, for example, ethyl or n-propylp-hydroxybenzoate; one or more colouring agents; one or more flavouringagents; and one or more sweetening agents such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, and preservative, such asmethyl and propyl parabens and flavouring and colouring agents.

The compounds of this invention may also be administered parenterally,that is, subcutaneously, intravenously, intraocularly, intrasynovially,intramuscularly, or interperitoneally, as injectable dosages of thecompound in preferably a physiologically acceptable diluent with apharmaceutical carrier which can be a sterile liquid or mixture ofliquids such as water, saline, aqueous dextrose and related sugarsolutions, an alcohol such as ethanol, isopropanol, or hexadecylalcohol, glycols such as propylene glycol or polyethylene glycol,glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4-methanol, etherssuch as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acidester or, a fatty acid glyceride, or an acetylated fatty acid glyceride,with or without the addition of a pharmaceutically acceptable surfactantsuch as a soap or a detergent, suspending agent such as pectin,carbomers, methycellulose, hydroxypropylmethylcellulose, orcarboxymethylcellulose, or emulsifying agent and other pharmaceuticaladjuvants.

Illustrative of oils which can be used in the parenteral formulations ofthis invention are those of petroleum, animal, vegetable, or syntheticorigin, for example, peanut oil, soybean oil, sesame oil, cottonseedoil, corn oil, olive oil, petrolatum and mineral oil. Suitable fattyacids include oleic acid, stearic acid, isostearic acid and myristicacid. Suitable fatty acid esters are, for example, ethyl oleate andisopropyl myristate. Suitable soaps include fatty acid alkali metal,ammonium, and triethanolamine salts and suitable detergents includecationic detergents, for example dimethyl dialkyl ammonium halides,alkyl pyridinium halides, and alkylamine acetates; anionic detergents,for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether,and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents,for example, fatty amine oxides, fatty acid alkanolamides, andpoly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxidecopolymers; and amphoteric detergents, for example,alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammoniumsalts, as well as mixtures.

The parenteral compositions of this invention will typically containfrom about 0.5% to about 25% by weight of the active ingredient insolution. Preservatives and buffers may also be used advantageously. Inorder to minimise or eliminate irritation at the site of injection, suchcompositions may contain a non-ionic surfactant having ahydrophile-lipophile balance (HLB) preferably of from about 12 to about17. The quantity of surfactant in such formulation preferably rangesfrom about 5% to about 15% by weight. The surfactant can be a singlecomponent having the above HLB or can be a mixture of two or morecomponents having the desired HLB.

Illustrative of surfactants used in parenteral formulations are theclass of polyethylene sorbitan fatty acid esters, for example, sorbitanmonooleate and the high molecular weight adducts of ethylene oxide witha hydrophobic base, formed by the condensation of propylene oxide withpropylene glycol.

The pharmaceutical compositions may be in the form of sterile injectableaqueous suspensions. Such suspensions may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents such as, for example, sodium carboxymethylcellulose,methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents which may be a naturally occurring phosphatide such aslecithin, a condensation product of an alkylene oxide with a fatty acid,for example, polyoxyethylene stearate, a condensation product ofethylene oxide with a long chain aliphatic alcohol, for example,heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxidewith a partial ester derived form a fatty acid and a hexitol such aspolyoxyethylene sorbitol monooleate, or a condensation product of anethylene oxide with a partial ester derived from a fatty acid and ahexitol anhydride, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent. Diluents and solvents that may be employed are, for example,water, Ringer's solution, isotonic sodium chloride solutions andisotonic glucose solutions. In addition, sterile fixed oils areconventionally employed as solvents or suspending media. For thispurpose, any bland, fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid can be usedin the preparation of injectables.

A composition of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritationexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are, for example, cocoa butter and polyethyleneglycol.

Controlled release formulations for parenteral administration includeliposomal, polymeric microsphere and polymeric gel formulations that areknown in the art.

It may be desirable or necessary to introduce the pharmaceuticalcomposition to the patient via a mechanical delivery device. Theconstruction and use of mechanical delivery devices for the delivery ofpharmaceutical agents is well known in the art. Direct techniques foradministration, for example, administering a drug directly to the brainusually involve placement of a drug delivery catheter into the patient'sventricular system to bypass the blood-brain barrier. One suchimplantable delivery system, used for the transport of agents tospecific anatomical regions of the body, is described in U.S. Pat. No.5,011,472, issued Apr. 30, 1991.

The compositions of the invention can also contain other conventionalpharmaceutically acceptable compounding ingredients, generally referredto as carriers or diluents, as necessary or desired. Conventionalprocedures for preparing such compositions in appropriate dosage formscan be utilized.

Such ingredients and procedures include those described in the followingreferences, each of which is incorporated herein by reference: Powell,M. F. et al., “Compendium of Excipients for Parenteral Formulations” PDAJournal of Pharmaceutical Science & Technology 1998, 52(5), 238-311;Strickley, R. G “Parenteral Formulations of Small Molecule TherapeuticsMarketed in the United States (1999)-Part-1” PDA Journal ofPharmaceutical Science & Technology 1999, 53(6), 324-349; and Nema, S.et al., “Excipients and Their Use in Injectable Products” PDA Journal ofPharmaceutical Science & Technology 1997, 51(4), 166-171.

Commonly used pharmaceutical ingredients that can be used as appropriateto formulate the composition for its intended route of administrationinclude:

acidifying agents (examples include but are not limited to acetic acid,citric acid, fumaric acid, hydrochloric acid, nitric acid);alkalinizing agents (examples include but are not limited to ammoniasolution, ammonium carbonate, diethanolamine, monoethanolamine,potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide,triethanolamine, trolamine);adsorbents (examples include but are not limited to powdered celluloseand activated charcoal);aerosol propellants (examples include but are not limited to carbondioxide, CCl₂F₂, F₂ClC—CClF₂ and CClF₃)air displacement agents—examples include but are not limited to nitrogenand argon;antifungal preservatives (examples include but are not limited tobenzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben,sodium benzoate);antimicrobial preservatives (examples include but are not limited tobenzalkonium chloride, benzethonium chloride, benzyl alcohol,cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol,phenylmercuric nitrate and thimerosal);antioxidants (examples include but are not limited to ascorbic acid,ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene,hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate,sodium bisulfite, sodium formaldehyde sulfoxylate, sodiummetabisulfite);binding materials (examples include but are not limited to blockpolymers, natural and synthetic rubber, polyacrylates, polyurethanes,silicones, polysiloxanes and styrene-butadiene copolymers);buffering agents (examples include but are not limited to potassiummetaphosphate, dipotassium phosphate, sodium acetate, sodium citrateanhydrous and sodium citrate dihydrate);carrying agents (examples include but are not limited to acacia syrup,aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orangesyrup, syrup, corn oil, mineral oil, peanut oil, sesame oil,bacteriostatic sodium chloride injection and bacteriostatic water forinjection);chelating agents (examples include but are not limited to edetatedisodium and edetic acid);colourants (examples include but are not limited to FD&C Red No. 3, FD&CRed No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&COrange No. 5, D&C Red No. 8, caramel and ferric oxide red);clarifying agents (examples include but are not limited to bentonite);emulsifying agents (examples include but are not limited to acacia,cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitanmonooleate, polyoxyethylene 50 monostearate);encapsulating agents (examples include but are not limited to gelatinand cellulose acetate phthalate),flavourants (examples include but are not limited to anise oil, cinnamonoil, cocoa, menthol, orange oil, peppermint oil and vanillin);humectants (examples include but are not limited to glycerol, propyleneglycol and sorbitol);levigating agents (examples include but are not limited to mineral oiland glycerin);oils (examples include but are not limited to arachis oil, mineral oil,olive oil, peanut oil, sesame oil and vegetable oil);ointment bases (examples include but are not limited to lanolin,hydrophilic ointment, polyethylene glycol ointment, petrolatum,hydrophilic petrolatum, white ointment, yellow ointment, and rose waterointment);penetration enhancers (transdermal delivery) (examples include but arenot limited to monohydroxy or polyhydroxy alcohols, mono- or polyvalentalcohols, saturated or unsaturated fatty alcohols, saturated orunsaturated fatty esters, saturated or unsaturated dicarboxylic acids,essential oils, phosphatidyl derivatives, cephalin, terpenes, amides,ethers, ketones and ureas),plasticizers (examples include but are not limited to diethyl phthalateand glycerol);solvents (examples include but are not limited to ethanol, corn oil,cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanutoil, purified water, water for injection, sterile water for injectionand sterile water for irrigation);stiffening agents (examples include but are not limited to cetylalcohol, cetyl esters wax, microcrystalline wax, paraffin, stearylalcohol, white wax and yellow wax);suppository bases (examples include but are not limited to cocoa butterand polyethylene glycols (mixtures));surfactants (examples include but are not limited to benzalkoniumchloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium laurylsulfate and sorbitan mono-palmitate);suspending agents (examples include but are not limited to agar,bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,kaolin, methylcellulose, tragacanth and veegum);sweetening agents (examples include but are not limited to aspartame,dextrose, glycerol, mannitol, propylene glycol, saccharin sodium,sorbitol and sucrose);tablet anti-adherents (examples include but are not limited to magnesiumstearate and talc);tablet binders (examples include but are not limited to acacia, alginicacid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose,gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinylpyrrolidone, and pregelatinized starch);tablet and capsule diluents (examples include but are not limited todibasic calcium phosphate, kaolin, lactose, mannitol, microcrystallinecellulose, powdered cellulose, precipitated calcium carbonate, sodiumcarbonate, sodium phosphate, sorbitol and starch);tablet coating agents (examples include but are not limited to liquidglucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetatephthalate and shellac);tablet direct compression excipients (examples include but are notlimited to dibasic calcium phosphate);tablet disintegrants (examples include but are not limited to alginicacid, carboxymethylcellulose calcium, microcrystalline cellulose,polacrillin potassium, cross-linked polyvinylpyrrolidone, sodiumalginate, sodium starch glycollate and starch);tablet glidants (examples include but are not limited to colloidalsilica, corn starch and talc);tablet lubricants (examples include but are not limited to calciumstearate, magnesium stearate, mineral oil, stearic acid and zincstearate);tablet/capsule opaquants (examples include but are not limited totitanium dioxide);tablet polishing agents (examples include but are not limited to carnubawax and white wax);thickening agents (examples include but are not limited to beeswax,cetyl alcohol and paraffin);tonicity agents (examples include but are not limited to dextrose andsodium chloride);viscosity increasing agents (examples include but are not limited toalginic acid, bentonite, carbomers, carboxymethylcellulose sodium,methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth);andwetting agents (examples include but are not limited toheptadecaethylene oxycetanol, lecithins, sorbitol monooleate,polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

Pharmaceutical compositions according to the present invention can beillustrated as follows:

Sterile i.v. Solution:

A 5 mg/mL solution of the desired compound of this invention can be madeusing sterile, injectable water, and the pH is adjusted if necessary.The solution is diluted for administration to 1-2 mg/mL with sterile 5%dextrose and is administered as an i.v. infusion over about 60 minutes.

Lyophilised Powder for i.v. Administration:

A sterile preparation can be prepared with (i) 100-1000 mg of thedesired compound of this invention as a lyophilised powder, (ii) 32-327mg/mL sodium citrate, and (iii) 300-3000 mg Dextran 40. The formulationis reconstituted with sterile, injectable saline or dextrose 5% to aconcentration of 10 to 20 mg/mL, which is further diluted with saline ordextrose 5% to 0.2-0.4 mg/mL, and is administered either IV bolus or byIV infusion over 15-60 minutes.

Intramuscular Suspension:

The following solution or suspension can be prepared, for intramuscularinjection:

50 mg/mL of the desired, water-insoluble compound of this invention5 mg/mL sodium carboxymethylcellulose4 mg/mL TWEEN 809 mg/mL sodium chloride9 mg/mL benzyl alcohol

Hard Shell Capsules:

A large number of unit capsules are prepared by filling standardtwo-piece hard galantine capsules each with 100 mg of powdered activeingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesiumstearate.

Soft Gelatin Capsules:

A mixture of active ingredient in a digestible oil such as soybean oil,cottonseed oil or olive oil is prepared and injected by means of apositive displacement pump into molten gelatin to form soft gelatincapsules containing 100 mg of the active ingredient. The capsules arewashed and dried. The active ingredient can be dissolved in a mixture ofpolyethylene glycol, glycerin and sorbitol to prepare a water misciblemedicine mix.

Tablets:

A large number of tablets are prepared by conventional procedures sothat the dosage unit is 100 mg of active ingredient, 0.2 mg. ofcolloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg ofmicrocrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose.Appropriate aqueous and non-aqueous coatings may be applied to increasepalatability, improve elegance and stability or delay absorption.

Immediate Release Tablets/Capsules:

These are solid oral dosage forms made by conventional and novelprocesses. These units are taken orally without water for immediatedissolution and delivery of the medication. The active ingredient ismixed in a liquid containing ingredient such as sugar, gelatin, pectinand sweeteners. These liquids are solidified into solid tablets orcaplets by freeze drying and solid state extraction techniques. The drugcompounds may be compressed with viscoelastic and thermoelastic sugarsand polymers or effervescent components to produce porous matricesintended for immediate release, without the need of water.

Dose and Administration

Based upon standard laboratory techniques known to evaluate compoundsuseful for the treatment of hyper-proliferative disorders and angiogenicdisorders, by standard toxicity tests and by standard pharmacologicalassays for the determination of treatment of the conditions identifiedabove in mammals, and by comparison of these results with the results ofknown medicaments that are used to treat these conditions, the effectivedosage of the compounds of this invention can readily be determined fortreatment of each desired indication. The amount of the activeingredient to be administered in the treatment of one of theseconditions can vary widely according to such considerations as theparticular compound and dosage unit employed, the mode ofadministration, the period of treatment, the age and sex of the patienttreated, and the nature and extent of the condition treated.

The total amount of the active ingredient to be administered willgenerally range from about 0.001 mg/kg to about 200 mg/kg body weightper day, and preferably from about 0.01 mg/kg to about 20 mg/kg bodyweight per day. Clinically useful dosing schedules will range from oneto three times a day dosing to once every four weeks dosing. Inaddition, “drug holidays” in which a patient is not dosed with a drugfor a certain period of time, may be beneficial to the overall balancebetween pharmacological effect and tolerability. A unit dosage maycontain from about 0.5 mg to about 1500 mg of active ingredient, and canbe administered one or more times per day or less than once a day. Theaverage daily dosage for administration by injection, includingintravenous, intramuscular, subcutaneous and parenteral injections, anduse of infusion techniques will preferably be from 0.01 to 200 mg/kg oftotal body weight. The average daily rectal dosage regimen willpreferably be from 0.01 to 200 mg/kg of total body weight. The averagedaily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kgof total body weight. The average daily topical dosage regimen willpreferably be from 0.1 to 200 mg administered between one to four timesdaily. The transdermal concentration will preferably be that required tomaintain a daily dose of from 0.01 to 200 mg/kg. The average dailyinhalation dosage regimen will preferably be from 0.01 to 100 mg/kg oftotal body weight.

Of course the specific initial and continuing dosage regimen for eachpatient will vary according to the nature and severity of the conditionas determined by the attending diagnostician, the activity of thespecific compound employed, the age and general condition of thepatient, time of administration, route of administration, rate ofexcretion of the drug, drug combinations, and the like. The desired modeof treatment and number of doses of a compound of the present inventionor a pharmaceutically acceptable salt or ester or composition thereofcan be ascertained by those skilled in the art using conventionaltreatment tests.

Combination Therapies

The compounds of this invention can be administered as the solepharmaceutical agent or in combination with one or more otherpharmaceutical agents where the combination causes no unacceptableadverse effects. Those combined pharmaceutical agents can be otheragents having antiproliferative effects such as for example for thetreatment of haematological tumours, solid tumours and/or metastasesthereof and/or agents for the treatment of undesired side effects. Thepresent invention relates also to such combinations.

Other anti-hyper-proliferative agents suitable for use with thecomposition of the invention include but are not limited to thosecompounds acknowledged to be used in the treatment of neoplasticdiseases in Goodman and Gilman's The Pharmacological Basis ofTherapeutics (Ninth Edition), editor Molinoff et al., publ. byMcGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated byreference, especially (chemotherapeutic) anti-cancer agents as definedsupra. The combination can be a non-fixed combination or a fixed-dosecombination as the case may be.

Methods of testing for a particular pharmacological or pharmaceuticalproperty are well known to persons skilled in the art.

The example testing experiments described herein serve to illustrate thepresent invention and the invention is not limited to the examplesgiven.

As will be appreciated by persons skilled in the art, the invention isnot limited to the particular embodiments described herein, but coversall modifications of said embodiments that are within the spirit andscope of the invention as defined by the appended claims.

The following examples illustrate the invention in greater detail,without restricting it. Further compounds according to the invention, ofwhich the preparation is not explicitly described, can be prepared in ananalogous way.

The compounds, which are mentioned in the examples and the salts thereofrepresent preferred embodiments of the invention as well as a claimcovering all subcombinations of the residues of the compound of formula(I) as disclosed by the specific examples.

The term “according to” within the experimental section is used in thesense that the procedure referred to is to be used “analogously to”.

EXPERIMENTAL PART

The following table lists the abbreviations used in this paragraph andin the Intermediate Examples and Examples section as far as they are notexplained within the text body.

Abbreviation Meaning br broad CI chemical ionisation d doublet dddoublet of doublet DAD diode array detector DCM dichloromethane DMFN,N-dimethylformamide DMSO dimethyl sulfoxide ELSD Evaporative LightScattering Detector eq. equivalent ESI electrospray (ES) ionisation hhours HPLC high performance liquid chromatography LC-MS liquidchromatography mass spectrometry m multiplet min minutes MS massspectrometry NMR nuclear magnetic resonance spectroscopy : chemicalshifts (δ) are given in ppm. The chemical shifts were corrected bysetting the DMSO signal to 2.50 ppm using unless otherwise stated. PDAPhoto Diode Array PoraPak ™; a HPLC column obtainable from Waters qquartet r.t. or rt room temperature RT retention time (as measuredeither with HPLC or UPLC) in minutes s singlet SM starting material SQDSingle-Quadrupol-Detector t triplet THF tetrahydrofuran UPLC ultraperformance liquid chromatography

Other abbreviations have their meanings customary per se to the skilledperson. The various aspects of the invention described in thisapplication are illustrated by the following examples which are notmeant to limit the invention in any way.

Specific Experimental Descriptions

NMR peak forms in the following specific experimental descriptions arestated as they appear in the spectra, possible higher order effects havenot been considered. Reactions employing microwave irradiation may berun with a Biotage Initator® microwave oven optionally equipped with arobotic unit. The reported reaction times employing microwave heatingare intended to be understood as fixed reaction times after reaching theindicated reaction temperature. The compounds and intermediates producedaccording to the methods of the invention may require purification.Purification of organic compounds is well known to the person skilled inthe art and there may be several ways of purifying the same compound. Insome cases, no purification may be necessary. In some cases, thecompounds may be purified by crystallization. In some cases, impuritiesmay be stirred out using a suitable solvent. In some cases, thecompounds may be purified by chromatography, particularly flash columnchromatography, using for example prepacked silica gel cartridges, e.g.from Separtis such as Isolute® Flash silica gel or Isolute® Flash NH₂silica gel in combination with a Isolera® autopurifier (Biotage) andeluents such as gradients of e.g. hexane/ethyl acetate or DCM/methanol.In some cases, the compounds may be purified by preparative HPLC usingfor example a Waters autopurifier equipped with a diode array detectorand/or on-line electrospray ionization mass spectrometer in combinationwith a suitable prepacked reverse phase column and eluents such asgradients of water and acetonitrile which may contain additives such astrifluoroacetic acid, formic acid or aqueous ammonia. In some cases,purification methods as described above can provide those compounds ofthe present invention which possess a sufficiently basic or acidicfunctionality in the form of a salt, such as, in the case of a compoundof the present invention which is sufficiently basic, a trifluoroacetateor formate salt for example, or, in the case of a compound of thepresent invention which is sufficiently acidic, an ammonium salt forexample. A salt of this type can either be transformed into its freebase or free acid form, respectively, by various methods known to theperson skilled in the art, or be used as salts in subsequent biologicalassays. It is to be understood that the specific form (e.g. salt, freebase etc) of a compound of the present invention as isolated asdescribed herein is not necessarily the only form in which said compoundcan be applied to a biological assay in order to quantify the specificbiological activity.

The percentage yields reported in the following examples are based onthe starting component that was used in the lowest molar amount. Air andmoisture sensitive liquids and solutions were transferred via syringe orcannula, and introduced into reaction vessels through rubber septa.Commercial grade reagents and solvents were used without furtherpurification. The term “concentrated in vacuo” refers to use of a Buchirotary evaporator at a minimum pressure of approximately 15 mm of Hg.All temperatures are reported uncorrected in degrees Celsius (° C.).

In order that this invention may be better understood, the followingexamples are set forth. These examples are for the purpose ofillustration only, and are not to be construed as limiting the scope ofthe invention in any manner. All publications mentioned herein areincorporated by reference in their entirety.

Analytical LC-MS Conditions

LC-MS-data given in the subsequent specific experimental descriptionsrefer (unless otherwise noted) to the following conditions:

System: Waters Acquity UPLC-MS: Binary Solvent Manager, SampleManager/Organizer, Column Manager, PDA, ELSD, SQD 3001 or ZQ4000 Column:Acquity UPLC BEH C18 1.7 50 × 2.1 mm Solvent: A1 = water + 0.1% vol.formic acid (99%) A2 = water + 0.2% vol. ammonia (32%) B1 = acetonitrileGradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B Flow: 0.8 mL/minTemperature: 60° C. Injection: 2.0 μL Detection: DAD scan range 210-400nm -> Peaktable ELSD MS ESI+, ESI− Switch -> various scan ranges (ReportHeader) Methods: Method 1: A1 + B1 = C:\MassLynx\Mass_100_1000.flpMethod 2: A1 + B1 = C:\MassLynx\Mass_160_1000.flp Method 3: A1 + B1 =C:\MassLynx\Mass_160_2000.flp Method 4: A1 + B1 =C:\MassLynx\Mass_160_1000_BasicReport.flp Method 5: A2 + B1 =C:\MassLynx\ NH₃_Mass_100_1000.flp Method 6: A2 + B1 =C:\MassLynx\NH₃_Mass_160-_1000_BasicReport.flp

Preparative HPLC Conditions

“Purification by preparative HPLC” in the subsequent specificexperimental descriptions refers to (unless otherwise noted) thefollowing conditions:

Analytics (Pre- and Post Analytics: Method B):

System: Waters Aqcuity UPLC-MS: Binary Solvent Manager, SampleManager/Organizer, Column Manager, PDA, ELSD, SQD 3001 Column: AqcuityBEH C18 1.7 50 × 2.1 mm Solvent: A = water + 0.1% vol. formic acid (99%)B = acetonitrile Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B Flow:0.8 mL/min Temperature: 60° C. Injection: 2 μL Detection: DAD scan range210-400 nm MS ESI+, ESI−, scan range 160-1000 m/z ELSD Methods:Purify_pre.flp Purify_post.flp

Preparation:

System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767,CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 μm 100 × 30 mmSolvent: A = water + 0.1% vol. formic acid (99%) B = acetonitrileGradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/minTemperature: RT Solution: max. 250 mg/2.5 mL dimethyl sufoxide or DMFInjection: 1 × 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+,ESI−, scan range 160-1000 m/z

Chiral HPLC Conditions

If not specified otherwise, chiral HPLC-data given in the subsequentspecific experimental descriptions refer to the following conditions:

Analytics:

System: Dionex: Pump 680, ASI 100, Waters: UV-Detektor 2487 Column:Chiralpak IC 5 μm 150 × 4.6 mm Solvent: hexane/ethanol 80:20 + 0.1%diethylamine Flow: 1.0 mL/min Temperature: 25° C. Solution: 1.0 mg/mLethanol/methanol 1:1 Injection: 5.0 μL Detection: UV 280 nm

Preparation:

System: Agilent: Prep 1200, 2xPrep Pump, DLA, MWD, Prep FC, ESA: CoronaColumn: Chiralpak IC 5 μm 250 × 30 mm Solvent: hexane/ethanol 80:20 +0.1% diethylamine Flow: 40 mL/min Temperature: RT Solution: 660 mg/5.6mL ethanol Injection: 8 × 0.7 mL Detection: UV 280 nm

Flash Column Chromatography Conditions

“Purification by (flash) column chromatography” as stated in thesubsequent specific experimental descriptions refers to the use of aBiotage Isolera purification system. For technical specifications see“Biotage product catalogue” on www.biotage.com.

Determination of Optical Rotation Conditions

Optical rotations were measured in dimethyl sulfoxide at 589 nmwavelength, 20° C., concentration 1.0000 g/100 mL, integration time 10s, film thickness 100.00 mm.

EXAMPLES Synthetic Intermediates Intermediate 1-1-1 Preparation of5′-cyclopropyl-1′-(4-ethoxy-2,6-difluorobenzyl)-4′-methyl-1-[2-(morpholin-4-yl)ethyl]-1H,1′H-3,3′-bipyrazol-5-amine

A solution of compound 1-2-1 (500 mg, 1.39 mmol, 1.0 eq.),4-(2-hydrazinylethyl)morpholine (202 mg, 1.39 mmol 1.0 eq.) andtriethylamine (186 μL, 1.33 mmol, 0.96 eq.) in ethanol (8.0 mL) wasrefluxed under an argon atmosphere overnight. To the reaction mixturewas added triethylamine (186 μL, 1.33 mmol, 0.96 eq.) again and themixture was refluxed overnight once more. After cooling to roomtemperature the mixture was concentrated in vacuo and the residue waspurified by preparative HPLC to yield the desired compound 1-1-1analytically pure (117 mg, 17%).

¹H NMR (300 MHz, DMSO-d₆) δ [ppm]=0.67 (d, 2H), 0.99 (dd, 2H), 1.30 (t,3H), 1.61-1.69 (m, 1H), 2.13 (s, 3H), 2.35-2.43 (m, 4H), 2.59 (t, 2H),3.49-3.61 (m, 4H), 3.95 (t, 2H), 4.04 (q, 2H), 5.15 (s, 2H), 5.26 (s,2H), 5.39 (s, 1H), 6.72 (d, 2H).

The following compounds were prepared according to the same procedurefrom the indicated starting materials (SM=starting material):

1-1-2 SM = 1-2-1

ethyl [5-amino- 5′-cyclopropyl-1′- (4-ethoxy-2,6- difluorobenzyl)-4′-methyl- 1H,1′H-3,3′- bipyrazol-1- yl]acetate ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 0.63-0.71 (m, 2 H), 0.95-1.04 (m, 2 H), 1.19 (t, 3H), 1.31 (t, 3 H), 1.59-1.72 (m, 1 H), 2.12 (s, 3 H), 4.05 (q, 2 H),4.12 (q, 2 H), 4.73 (s, 2 H), 5.18 (s, 2 H), 5.27 (s, 2 H), 5.41 (s, 1H), 6.67-6.75 (m, 2 H).

Intermediate 1-1-3 Preparation of1-[5-amino-5′-cyclopropyl-1′-(4-ethoxy-2,6-difluorobenzyl)-4′-methyl-1H,1′H-3,3′-bipyrazol-1-yl]ethanone

A solution of nitrile 1-2-1 (121 mg, 337 μmol, 1.3 eq.) andacethydrazide (90%, 30.5 mg, 370 μmol, 1.1 eq.) in acetic acid (1.05 mL,33.7 mmol, 100 eq) was stirred overnight at 90 to 110° C. Although thereaction was not completed, the mixture was diluted with water. Therebya precipitate was formed which was filtrated off and washed subsequentwith water and some ethanol. The crude product was purified by flashchromatography to obtain the desired compound 1-1-3 as white solid (27mg, 18%).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.65-0.75 (m, 2H), 0.97-1.06 (m, 2H),1.31 (t, 3H), 1.62-1.71 (m, 1H), 1.99 (s, 3H), 2.08 (br. s, 3H),4.01-4.09 (m, 2H), 5.34 (s, 2H), 6.58 (br. s, 1H), 6.69-6.75 (m, 2H),10.32 (br. s, 1H), 12.26 (s, 1H).

Intermediate 1-1-4 Preparation of N-{5′-cyclopropyl-1′-(4-ethoxy-2,6-difluorobenzyl)-4′-methyl-1-[2-(methylsulfonyl)ethyl]-1H,1′H-3,3′-bipyrazol-5-yl}acetamide

To a solution of nitrile 1-2-1 (421 mg, 1.71 mmol, 1.0 eq.) in aceticacid (6.7 mL, 117 mmol, 100 eq.) was added(2-methanesulfonylethyl)hydrazine hydrochloride (307 mg, 1.75 mmol, 1.5eq.). The reaction mixture was stirred at 90° C. for 4 days. Aftercooling to room temperature the mixture was diluted with water andconcentrated in vacuo. The residue was purified by flash chromatographyto yield analytically pure the desired compound (134 mg, 22%).

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.63-0.76 (m, 2H), 0.96-1.07 (m, 2H),1.30 (t, 3H), 1.57-1.74 (m, 1H), 2.08 (s, 3H), 2.18 (s, 3H), 2.91 (s,3H), 3.61 (t, 2H), 4.04 (q, 2H), 4.41 (t, 2H), 5.30 (s, 2H), 6.31 (s,1H), 6.73 (d, 2H), 10.00 (s, 1H).

Intermediate 1-1-5 Preparation of5′-cyclopropyl-1′-(4-ethoxy-2,6-difluorobenzyl)-4′-methyl-1-[2-(methylsulfonyl)ethyl]-1H,1′H-3,3′-bipyrazol-5-amine

To a solution of compound 1-1-4 (116 mg, 222 μmol, 1.0 eq.) in methanol(900 μL) was added 2M aqueous hydrochloric acid (111 μL, 222 μmol, 1.0eq.). The mixture was stirred at 60° C. for 3 days and subsequentconcentrated in vacuo to obtain the desired amine (100 mg, 90%).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.70 (dd, 2H), 1.02 (dd, 2H), 1.31(t, 3H), 1.58-1.71 (m, 1H), 2.14 (s, 3H), 3.00 (s, 3H), 3.60 (s, 2H),4.05 (d, 2H), 4.43 (s, 2H), 5.35 (s, 2H), 5.67 (s, 1H), 6.73 (d, 2H).

Intermediate 1-1-6 Preparation of5′-cyclopropyl-1′-(4-ethoxy-2,6-difluorobenzyl)-1,4′-dimethyl-1H,1′H-3,3′-bipyrazol-5-amine

120 mg of3-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-3-oxopropanenitrile1-2-1 (0.334 mmol, 1.0 eq.) and 23 mg of methyl-hydrazine (0.501 mmol,1.5 eq.) were dissolved in 1 mL methanol in microwave tube. The reactionmixture stirred at 160° C. for 15 min in a microwave oven, afterwards itwas concentrated in vacuo. The residue was purified by chromatography toprovide 54 mg (40%, 0.14 mmol) of the 97% pure target compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.58-0.68 (m, 2H), 0.91-1.00 (m, 2H),1.27 (t, 3H), 1.55-1.67 (m, 1H), 2.10 (s, 3H), 3.46 (s, 3H), 4.01 (q,2H), 5.04 (s, 2H), 5.22 (s, 2H), 5.36 (s, 1H), 6.64-6.74 (m, 2H).

Intermediate 1-2-1 Preparation of3-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-3-oxopropanenitrile

A 1.6 M solution of n-butyllithium in hexane (36.9 mL, 59.0 mmol, 2.0eq.) was dropped to a solution of dry acetonitrile (6.2 mL, 118 mmol,4.0 eq.) in THF (250 mL) at −78° C. The colored mixture was stirred for1 h at this temperature. Afterwards a solution of compound 1-3-1 (10.3g, 29.5 mmol, 1.0 eq.) in THF (50 mL) was added. The reaction mixturewas allowed to warm up to room temperature and was stirred for 2 h. Themixture was diluted with ethyl acetate and extracted with water. Theaqueous layer was extracted again two times with ethyl acetate. Thecombined organic layers were washed with brine, dried over magnesiumsulfate and concentrated in vacuo to give the desired compound 1-2-1(10.6 g, 98%), which was used without further purification.

¹H NMR (300 MHz, DMSO-d₆) δ [ppm]=0.64-0.77 (m, 2H), 0.97-1.07 (m, 2H),1.31 (t, 3H), 1.61-1.70 (m, 1H), 2.12-2.22 (m, 3H), 4.05 (q, 2H), 4.30(s, 2H), 5.41 (s, 2H), 6.67-6.82 (m, 2H).

Intermediate 1-3-1 Preparation of methyl5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazole-3-carboxylate

To a solution of ester 1-4-1 (90.0 g, 463.4 mmol, 1.0 eq.) in THF (900mL) was added sodium hydride (60% in mineral oil, 22.2 g, 1.2 eq.) inportions to keep the temperature between 0-5° C. under an argonatmosphere. The ice bath was removed and the reaction mixture wasstirred for 30 min to give a slightly brown colored suspension.Afterwards 4-ethoxy-2,6-difluorbenzylbromide (116 g, 463 mmol, 1.0 eq.)was added and the reaction mixture was stirred for 2 h at roomtemperature. The mixture was carefully diluted with methanol andsubsequent dropped into water containing some sodium chloride (2 L). Thelayers were separated. The aqueous layer was washed three times withethyl acetate. The combined organic layers were washed withhalf-saturated sodium chloride solution, dried over magnesium sulfateand concentrated in vacuo to give the crude product, which was purifiedby digestion with pentan/diethylether 1:1. The desired compound 1-3-1was obtained, containing 8% of the corresponding ethyl ester (135 g,83%).

¹H NMR (300 MHz, DMSO-d₆) δ [ppm]=0.63-0.74 (m, 2H), 0.96-1.08 (m, 2H),1.24-1.36 (m, 3H), 1.61-1.74 (m, 1H), 2.16 (s, 3H), 3.71 (s, 3H), 4.05(q, 2H), 5.36 (s, 2H), 6.64-6.82 (m, 2H).

Intermediate 1-4-1 Preparation of ethyl5-cyclopropyl-4-methyl-1H-pyrazole-3-carboxylate

To 10.0 g of ethyl 4-cyclopropyl-3-methyl-2,4-dioxobutanoate 1-6-1 (51mmol, 1.0 eq.) in 100 mL ethanol were added 3.16 g hydrazine hydrate(80%, 50.4 mmol, 1.0 eq.). The reaction mixture was stirred at 70° C.for 1 h under nitrogen. The solids were filtered off and the filtratewas concentrated in vacuo. The residue was dissolved in 100 mL diethylether and 50 mL 2 M hydrochloric acid in diethyl ether was added. Afterstirring for 2 hours at rt the product was filtered off and dried at 40°C. in vacuo to provide 7.40 g (32 mmol, 66%) of analytically pure targetcompound.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.62-0.72 (m, 2H), 0.81-0.87 (m, 2H),1.24 (t, 3H), 1.69-1.83 (m, 1H), 2.16 (s, 3H), 4.21 (q, 2H)

Intermediate 1-6-1 Preparation of ethyl4-cyclopropyl-3-methyl-2,4-dioxobutanoate

165 mL of an 1 M solution of bis(trimethylsilyl)lithiumamid in THF (166mmol, 1.10 eq.) were added to 500 mL of diethyl ether and cooled down to78° C. 14.8 g of 1-cyclopropylpropan-1-one 1-7-1 (150 mmol, 1.0 eq.)were dissolved in 100 mL of diethyl ether and added dropwise at −78° C.The mixture was stirred for one hour at −78° C. and then 24.5 mL ofdiethyl oxalate (181 mmol, 1.2 eq.) were added dropwise. The coolingbath was removed and the mixture was stirred for 24 hours at rt. 500 mLof aqueous 1M hydrogen chloride solution was added and the mixture wasextracted with DCM, dried over a silicone filter and concentrated invacuo to provide 27.2 g (137 mmol, 91%) of the target compound as crudeproduct. The crude product was used for the following step withoutfurther purification.

Intermediate 1-7-1 Preparation of 1-cyclopropylpropan-1-one

198 mL of a 3M ethylmagnesium bromide solution in diethyl ether (596mmol, 1.0 eq.) was cooled to 0° C. and 44.2 mL ofcyclopropanecarbonitrile dissolved in 80 mL of dry diethyl ether wasadded dropwise. The mixture was stirred at reflux for 6 hours. It washydrolysed with aqueous saturated ammonium chloride solution and stirredfor 24 hours at rt. The resulting suspension was filtered off and washedwith diethyl ether. The filtrate was dried over sodium sulfate andconcentrated in vacuo (at 40° C. bath temperature and 600 mbar).Distillation of the crude product in vacuo provided 36.9 g (376 mmol,63%) of analytically pure target compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.73-0.84 (m, 4H), 0.91 (t, 3H),1.91-2.02 (m, 1H), 2.52 (q, 2H).

Intermediate 1-8-1 Preparation of3-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-1-(2-methoxyethyl)-1H-1,2,4-triazol-5-amine

623 mg of3-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-1H-1,2,4-triazol-5-aminehydrochloride 1-9-1 (1.5 mmol, 1.0 eq.) were dissolved in 12 mL DMF.1.05 g of potassium carbonate (7.58 mmol, 5.0 eq.) and 211 mg2-bromoethyl methyl ether (1.5 mmol, 1.0 eq.) were added and thereaction mixture was stirred at 60° C. overnight. Water and ethylacetate were added and the layers were separated. The aqueous layer wasextracted with ethyl acetate twice. The combined organic layers weredried over a silicon filter and the filtrate was concentrated in vacuoto provide the crude product. The crude product was purified bychromatography to yield 301 mg (41%, 0.62 mmol) of the 89% pure targetcompound.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.60-0.71 (m, 2H), 0.92-1.04 (m, 2H),1.27 (t, 3H), 1.57-1.73 (m, 1H), 2.13 (s, 3H), 3.18 (s, 3H), 3.55 (t,2H), 3.90-4.09 (m, 4H), 5.24 (s, 2H), 6.05 (s, 2H), 6.64-6.77 (m, 2H).

The following compounds were prepared according to the same procedurefrom the indicated starting materials (SM=starting material):

1-8-2 SM = 1-9-1

1-(2-{[tert- butyl(dimethyl)- silyl]oxy}ethyl)-3- [5-cyclopropyl-1-(4-ethoxy-2,6- difluorobenzyl)- 4-methyl-1H- pyrazol-3-yl]-1H-1,2,4-triazol-5- amine ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.07 (s,6H), 0.66-0.74 (m, 2H), 0.80 (s, 9H), 0.97-1.04 (m, 2H), 1.30 (t, 3H),1.63-1.72 (m, 1H), 2.15 (s, 3H), 3.82 (t, 2H), 3.94 (t, 2H), 4.04 (q,2H), 5.27 (s, 2H), 6.01 (s, 2H), 6.69- 6.75 (m, 2H).

Intermediate 1-9-1 Preparation of3-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-1H-1,2,4-triazol-5-aminehydrochloride

0.76 g of sodium (33 mmol, 4.0 eq.) were added slowly to 35 mL methanoland stirred under nitrogen until sodium completely disappeared. Then thesolution was cooled to 0° C. and 4.1 g of aminoguanidine hemisulfate (16mmol, 2.0 eq.) were added and stirred for 10 min. Afterwards 3.0 g ofethyl5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazole-3-carboxylate1-10-1 (8.2 mmol, 1.0 eq.) dissolved in 15 mL methanol were addeddropwise, the reaction mixture was allowed to warm to rt and stirredunder reflux overnight. The reaction mixture was cooled to 0° C. until aprecipitate was built, filtered off and washed with methanol. Thecombined filtrate was concentrated in vacuo, purified by chromatographyto provide 97% pure target compound (1.06 g, 31%, 2.54 mmol).

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.60-0.72 (m, 2H), 0.94-1.00 (m, 2H),1.27 (t, 3H), 1.55-1.72 (m, 1H), 2.13 (s, 3H), 4.01 (q, 2H), 5.26 (br.s, 2H), 5.84 (br. s, 2H), 6.66-6.74 (m, 2H), 11.84 (br. s, 1H).

Intermediate 1-10-1 Preparation of ethyl5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazole-3-carboxylate

A solution of ethyl 5-cyclopropyl-4-methyl-1H-pyrazole-3-carboxylate1-4-1 (46.9 g, 266 mmol, 1.0 eq.) in THF (588 mL) were cooled to 0° C.and sodium hydride (60%, 11.6 g 290 mmol, 1.2 eq.) were added in smallportions. The resulting suspension was diluted with 250 mL THF.2-(Bromomethyl)-5-ethoxy-1,3-difluorobenzene (66.7 g, 266 mmol, 1.1 eq.)were added slowly. The reaction mixture was stirred at rt for 2 h. 300mL water was added and the THF was evaporated in vacuo. The aqueousresidue was extracted with ethyl acetate three times. The combinedorganic layers were dried over a silicone filter and concentrated invacuo. The residue was purified by flash chromatography to provide 79.8g (195 mmol, 81%) of 89% pure target compound.

¹H-NMR (400 MHz, CHLOROFORM-d): δ [ppm]=0.65-0.70 (m, 2H), 0.96-1.03 (m,2H), 1.34-1.42 (m, 7H), 1.47-1.52 (m, 1H), 2.24 (s, 3H), 3.97 (q, 3H),4.35 (q, 2H), 5.46 (s, 2H), 6.40-6.44 (m, 2H).

Intermediate 1-11-1 Preparation of3-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-1-(2-methoxyethyl)-1H-1,2,4-triazol-5-amine

115 mg of3-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-1H-1,2,4-triazol-5-amine1-12-1 (0.311 mmol, 1.0 eq.) were dissolved in 2.4 mL DMF. 215 mg ofpotassium carbonate (1.55 mmol, 5.0 eq.) and 43 mg 2-bromoethyl methylether (0.311 mmol, 1.0 eq.) were added and the reaction mixture wasstirred at 60° C. overnight. Water and ethyl acetate were added and thelayers were separated. The aqueous layer was extracted with ethylacetate twice. The combined organic layers were dried over a siliconfilter and the filtrate was concentrated in vacuo to provide the crudeproduct. The crude product was purified by chromatography to yield 49 mg(28%, 0.086 mmol) of the 75% pure target compound which was used withoutfurther purification.

Intermediate 1-11-2 Preparation of5-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-1-(2-methoxyethyl)-1H-1,2,4-triazol-3-amine

As a side product from the reaction to intermediate 1-11-15-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-1-(2-methoxyethyl)-1H-1,2,4-triazol-3-aminewas isolated: 34 mg (19%, 0.060 mmol) of the 63% pure target compound,which was used without further purification.

Intermediate 1-12-1 Preparation of3-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-1H-1,2,4-triazol-5-amine

0.37 g of sodium (12 mmol, 4.0 eq.) were added slowly to 12 mL methanoland stirred under nitrogen until sodium completely disappeared. Then thesolution was cooled to 0° C. and 0.43 g of aminoguanidine hemisulfate(5.8 mmol, 2.0 eq.) were added and stirred for 10 min. Afterwards 1.0 gof methyl 1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazole-3-carboxylate1-13-1 (2.9 mmol, 1.0 eq.) dissolved in 5 mL methanol were addeddropwise. The reaction mixture was allowed to warm to rt and stirredunder reflux overnight. The reaction mixture was cooled to 0° C. until aprecipitate was built, filtered off and washed with methanol. Thecombined filtrate was concentrated in vacuo, purified by chromatographyto provide 77% pure target compound (115 mg, 8%, 0.24 mmol).

¹H NMR (300 MHz, DMSO-d₆) δ [ppm]=1.25 (t, 3H), 4.00 (q, 2H), 5.56 (s,2H), 5.96-6.25 (m, 2H), 6.61-6.79 (m, 2H), 7.17 (t, 1H), 7.42 (t, 1H),7.71 (d, 1H), 8.18 (d, 1H), 12.19 (br. s, 1H).

Intermediate 1-13-1 Preparation of methyl1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazole-3-carboxylate

9.98 g of methyl 1H-indazole-3-carboxylate (CAS Reg. No.: 43120-28-1)(56.65 mmol, 1 eq.) were dissolved in 260 mL of dry tetrahydrofuran at0° C. 22.15 g of cesium carbonate (67.98 mmol, 1.2 eq.) and 15.65 g2-(bromomethyl)-1,3-difluorobenzene (62.31 mmol, 1.1 eq.) were added.The mixture was stirred at room temperature for five hours under anitrogen atmosphere. Then the reaction mixture was concentrated invacuo. The residue was partitioned between dichloromethane and halfsaturated aqueous sodium bicarbonate solution. The organic layer waswashed with water, dried over sodium sulfate and concentrated in vacuoyielding 21.18 g of the title compound (61.15 mmol, 108.0%). Thematerial was pure enough for further processing.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=1.26 (t, 3H), 3.86 (s, 3H), 4.01 (q,2H), 5.68 (s, 2H), 6.73 (“d”, 2H), 7.33 (“t”, 1H), 7.51 (“t”, 1H), 7.83(“d”, 1H), 8.04 (“d”, 1H).

The following compounds were prepared according to the same procedurefrom the indicated starting materials (SM=starting material):

1-13-2 SM = 3-iodo- 1H- indazole (CAS- Reg.- No.: 66607- 27-0)

1-(4-ethoxy-2,6- difluorobenzyl)- 3-iodo-1H- indazole ¹H-NMR (300 MHz,DMSO-d₆): δ [ppm] = 1.25 (t, 3H), 4.00 (q, 2H), 5.56 (s, 2H), 6.66- 6.76(m, 2H), 7.14-7.25 (m, 1H), 7.37 (d, 1H), 7.44-7.56 (m, 1H), 7.72 (d,1H).

Intermediate 1-14-1 Preparation of1-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-1H-pyrazol-4-amine

25 mg of1-(4-ethoxy-2,6-difluorobenzyl)-3-(4-nitro-1H-pyrazol-1-yl)-1H-indazole1-15-1 (0.063 mmol, 1.0 eq.) were dissolved in methanol and 21 mg raneynickel (50%, 0.125 mmol, 2.0 eq.) and 0.044 mL hydrazine hydrate (35%,0.313 mmol, 5.0 eq.) were added. The reaction mixture was stirred atroom temperature under argon for 4 h and was filtered through celite,washed with ethanol and the combined filtrates were concentrated invacuo. The 84% pure crude product was used without further purification:24 mg, 87%, 0.05 mmol.

¹H NMR (300 MHz, DMSO-d₆) δ [ppm]=1.25 (t, 3H), 3.99 (q, 2H), 4.23 (br.s, 2H), 5.50 (s, 2H), 6.70 (d, 2H), 7.14 (t, 1H), 7.31 (s, 1H),7.39-7.49 (m, 1H), 7.52 (s, 1H), 7.67 (d, 1H), 8.14 (d, 1H).

Intermediate 1-15-1 Preparation of1-(4-ethoxy-2,6-difluorobenzyl)-3-(4-nitro-1H-pyrazol-1-yl)-1H-indazole

Cesium carbonate was dried in a drying cabinet at 50° C. 200 mg of1-(4-Ethoxy-2,6-difluorobenzyl)-3-iodo-1H-indazole 1-13-2 (0.48 mmol,1.0 eq.), 109 mg of 4-nitro-1H-pyrazole (0.97 mmol, 2.0 eq.), 315 mg ofcesium carbonate (0.97 mmol, 2.0 eq.), 3.84 mg of copper (II) oxide(0.048 mmol, 0.1 eq.) and 51 mg of iron (III) acetyl acetonate (0.15mmol, 0.3 eq.) were dissolved in 1 mL DMF. The reaction mixture wasdegased and stirred in a microwave vial at 90° C. for 5 days. Water anddichloromethane were added and stirred for 5 min., then it was pouredthrough a silicon filter, concentrated in vacuo and purified by HPLC toprovide the analytically pure target compound: 25 mg, 13%, 0.06 mmol).

¹H NMR (300 MHz, DMSO-d₆) δ [ppm]=1.25 (t, 3H), 4.00 (q, 2H), 5.63 (s,2H), 6.65-6.77 (m, 2H), 7.29 (t, 1H), 7.56 (t, 1H), 7.83 (d, 1H), 8.02(d, 1H), 8.62 (s, 1H), 9.19 (s, 1H).

Intermediate 1-16-1 Preparation of3-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-1,2,4-thiadiazol-5-amine

150 mg of 1-(2-fluorobenzyl)-1H-indazole-3-carboximidamide hydrochloride(1:1) (CAS-Reg.-No.: 256376-75-7) (0.49 mmol, 1.0 eq.) were dissolved in2.68 ml of methanol and cooled to 0° C. At this temperature 0.17 ml oftriethylamine (1.23 mmol, 2.5 eq.), were added and the mixture stirredat 0° C. for 10 minutes. Then 33 mg of potassium thiocyanate (0.97 mmol,0.7 eq.) dissolved in 0.5 mL of methanol were added dropwise. Thecooling bath was removed and the mixture was allowed to come to roomtemperature, while forming a precipitate. The precipitate was filteredoff to provide the analytically pure target compound: 28 mg, 17%, 0.09mmol).

¹H NMR (300 MHz, DMSO-d₆) δ [ppm]=5.73 (s, 2H), 7.07-7.27 (m, 4H), 7.32(m, 1H), 7.43 (tbr, 1H), 7.75 (d, 1H), 8.03 (s, 2H), 8.33 (d, 1H).

Example Compounds Example 2-1-1 Preparation of5′-cyclopropyl-1′-(4-ethoxy-2,6-difluorobenzyl)-4′-methyl-1-[2-(morpholin-4-yl)ethyl]-N-(pyrimidin-4-yl)-1H,1′H-3,3′-bipyrazol-5-amine

To a suspension of 1-1-1 (114 mg, 234 μmol, 1.0 eq.) in DMF (901 μL)4-bromopyrimidine hydrochloride (51.9 mg, 258 μmol, 1.1 eq.), cesiumcarbonate (229 mg, 703 μmol, 3.0 eq.),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (20.3 mg, 35.1 μmol,0.15 eq.) and palladium(II) acetate (5.3 mg, 23.4 μmol, 0.1 eq.) wereadded under an argon atmosphere. The reaction mixture was stirred in asealed tube at 105° C. overnight. After cooling to room temperature themixture was filtrated off and concentrated in vacuo. The remainingmaterial was purified by preparative HPLC to yield the desired compound2-1-1 analytically pure (3.2 mg, 2.2%).

¹H NMR (300 MHz, DMSO-d₆) δ [ppm]=0.64-0.75 (m, 2H), 0.96-1.06 (m, 2H),1.30 (t, 3H), 1.60-1.73 (m, 1H), 2.19 (s, 3H), 2.35 (br. s, 4H),2.62-2.66 (m, 2H), 3.42-3.49 (m, 4H), 4.04 (q, 2H), 4.11-4.18 (m, 2H),5.31 (s, 2H), 6.34 (s, 1H), 6.78-6.71 (m, 3H), 8.31 (d, 1H), 8.61 (s,1H), 9.63 (s, 1H).

The following compounds were prepared according to the same procedurefrom the indicated starting materials (SM=starting material):

2-1-2 SM = 1-1-3

1-[5′-cyclopropyl- 1′-(4-ethoxy-2,6- difluorobenzyl)- 4′-methyl-5-(pyrimidin-4- ylamino)-1H,1′H- 3,3′-bipyrazol-1- yl]ethanone ¹H-NMR (300MHz, DMSO-d₆): δ [ppm] = 0.67-0.79 (m, 2 H), 0.97-1.12 (m, 2 H), 1.31(t, 3 H), 1.59-1.78 (m, 1 H), 2.24 (s, 3 H), 2.31 (s, 3 H), 4.05 (q, 2H), 5.37 (s, 2 H), 6.75 (d, 2 H), 6.96 (s, 1 H), 7.90 (dd, 1 H), 8.89(d, 1 H), 9.11 (d, 1 H), 11.52 (s, 1 H). 2-1-3 SM = 1-1-2

[5′-cyclopropyl- 1′-(4-ethoxy-2,6- difluorobenzyl)- 4′-methyl-5-(pyrimidin-4- ylamino)-1H,1′H- 3,3′-bipyrazol-1- yl]acetic acid ¹H-NMR(400 MHz, DMSO-d₆): δ [ppm] = 0.70 (dd, 2 H), 1.00 (dd, 2 H), 1.30 (t, 3H), 1.60- 1.72 (m, 1 H), 2.19 (s, 3 H), 4.05 (d, 2 H), 4.49 (s, 2 H),5.32 (s, 2 H), 6.45 (s, 1 H), 6.66-6.80 (m, 3 H), 6.85-7.43 (m, 1 H),8.27 (d, 1 H), 8.61 (d, 1 H), 10.79-11.76 (m, 1 H). 2-1-4 SM = 1-1-6

5′-cyclopropyl-1′- (4-ethoxy-2,6- difluorobenzyl)- 1,4′-dimethyl-N-(pyrimidin-4-yl)- 1H,1′H-3,3′- bipyrazol-5- amine ¹H-NMR (300 MHz,DMSO-d₆): δ [ppm] = 0.58-0.72 (m, 2H), 0.93- 1.06 (m, 2H), 1.27 (t, 3H),1.57-1.70 (m, 1H), 2.16 (s, 3H), 3.64 (s, 3H), 4.01 (q, 2H), 5.27 (s,2H), 6.33 (s, 1H), 6.62-6.76 (m, 3H), 8.27 (d, 1H), 8.51-8.66 (m, 1H),9.39 (br. s., 1H). 2-1-5 SM = 1-8-1

N-{3-[5- cyclopropyl-1-(4- ethoxy-2,6- difluorobenzyl)- 4-methyl-1H-pyrazol-3-yl]-1- (2- methoxyethyl)- 1H-1,2,4-triazol- 5-yl}pyrimidin-4-amine ¹H-NMR (300 MHz, DMSO-d₆): δ [ppm] = 0.64-0.72 (m, 2H), 0.92-1.05(m, 2H), 1.27 (t, 3H), 1.58-1.74 (m, 1H), 2.18 (s, 3H), 3.15 (s, 3H),3.62 (t, 2H), 4.01 (q, 2H), 4.28 (t, 2H), 5.32 (s, 2H), 6.67- 6.76 (m,2H), 7.59 (d, 1H), 8.45 (d, 1H), 8.67 (s, 1H), 10.19 (br. s., 1H).

Example 2-2-1 Preparation of5′-cyclopropyl-1′-(4-ethoxy-2,6-difluorobenzyl)-4′-methyl-1-[2-(methylsulfonyl)ethyl]-N-(pyrimidin-4-yl)-1H,1′H-3,3′-bipyrazol-5-amine

To a suspension of 1-1-5 (105 mg, 219 μmol, 1.0 eq.), 4-bromopyrimidinehydrochloride (47.0 mg, 241 μmol, 1.1 eq.), cesium carbonate (214 mg,657 μmol, 3.0 eq.) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene(19.0 mg, 33.0 μmol, 0.15 eq.) in DMF (1.7 mL) was added palladium(II)acetate (4.9 mg, 22 μmol, 0.1 eq.) under an argon atmosphere. Thereaction mixture was stirred in a sealed tube at 105° C. overnight.After cooling to room temperature 4-bromopyrimidine hydrochloride (47.0mg, 241 μmol, 1.1 eq.) and palladium(II) acetate (4.9 mg, 22 μmol, 0.1eq.) were added to the mixture and it was stirred for 3 h at 105° C.,for 3 days at room temperature and again for 3 h at 105° C. Aftercooling to ambient temperature the mixture was filtered, the filtratewas concentrated in vacuo and the residue was purified by preparativeHPLC to yield the desired compound 2-2-1 (2.0 mg, 1.5%).

¹H NMR (600 MHz, DMSO-d₆) δ [ppm]=0.73-0.78 (m, 2H), 1.03-1.09 (m, 2H),1.28-1.33 (m, 3H), 1.70-1.76 (m, 1H), 2.08 (s, 3H), 2.87 (s, 3H), 3.46(t, 2H), 4.05 (q, 2H), 4.56 (t, 2H), 5.39 (s, 2H), 6.57 (s, br., 1H),6.73 (d, 2H), 8.28 (d, 1H), 8.58 (s, 1H), 9.99 (s, 1H).

Example 2-3-1 Preparation of5′-cyclopropyl-1′-(4-ethoxy-2,6-difluorobenzyl)-1,4′-dimethyl-N-(pyridin-4-yl)-1H,1′H-3,3′-bipyrazol-5-amine

70 mg of5′-cyclopropyl-1′-(4-ethoxy-2,6-difluorobenzyl)-1,4′-dimethyl-1H,1′H-3,3′-bipyrazol-5-amine1-1-6 (0.18 mmol, 1.0 eq.) were dissolved in 0.7 mL DMF. 39 mg of4-bromo-pyridine hydrochloride (0.20 mmol, 1.1 eq.), 177 mg cesiumcarbonate (0.54 mmol, 3.0 eq.), 4.1 mg of palladium(II) acetate (0.018mmol, 0.1 eq.) and 16 mg of4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.027 mmol, 0.15 eq.)were added under an argon atmosphere. The reaction mixture was stirredin a sealed tube at 105° C. for 3 h. After cooling to ambienttemperature water and ethyl acetate were added. The layers wereseparated and the aqueous layer was extracted with ethyl acetate twice.The combined organic layers were dried over a silicon filter,concentrated in vacuo and the residue was purified by chromatography toyield the desired compound (61 mg, 72%, 0.13 mmol).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.64-0.68 (m, 2H), 0.94-1.02 (m, 2H),1.27 (t, 3H), 1.59-1.68 (m, 1H), 2.16 (s, 3H), 3.61 (s, 3H), 4.01 (q,2H), 5.27 (s, 2H), 6.12 (s, 1H), 6.63-6.73 (m, 4H), 8.16 (d, 2H), 8.62(s, 1H).

The following compounds were prepared according to the same procedurefrom the indicated starting materials (SM=starting material):

2-3-2 SM = 1-8-1

N-{3-[5- cyclopropyl-1-(4- ethoxy-2,6- difluorobenzyl)- 4-methyl-1H-pyrazol-3-yl]-1- (2- methoxyethyl)- 1H-1,2,4-triazol- 5-yl}pyridin-4-amine ¹H-NMR (300 MHz, DMSO-d₆): δ [ppm] = 0.63-0.74 (m, 2H), 0.92- 1.05(m, 2H), 1.27 (t, 3H), 1.59-1.72 (m, 1H), 2.20 (s, 3H), 3.17 (s, 3H),3.64 (t, 2H), 4.01 (q, 2H), 4.31 (t, 2H), 5.32 (s, 2H), 6.67-6.77 (m,2H), 7.54 (d, 2H), 8.30 (d, 2H), 9.37 (s, 1H). 2-3-3 SM = 1-8-2

2-{3-[5- cyclopropyl-1-(4- ethoxy-2,6- difluorobenzyl)- 4-methyl-1H-pyrazol-3-yl]-5- (pyridin-4- ylamino)-1H- 1,2,4-triazol-1- yl}ethanol¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.67-0.71 (m, 2H), 0.94-1.05 (m,2H), 1.27 (t, 3H), 1.59-1.72 (m, 1H), 2.20 (s, 3H), 3.71 (t, 2H), 4.02(q, 2H), 4.17 (t, 2H), 4.99 (br. s, 1H), 5.32 (s, 2H), 6.68- 6.73 (m,2H), 7.52 (d, 2H), 8.29 (d, 2H), 9.32 (br. s., 1H) 2-3-4 SM = 1-9-1

N-{3-[5- cyclopropyl-1-(4- ethoxy-2,6- difluorobenzyl)- 4-methyl-1H-pyrazol-3-yl]-1H- 1,2,4-triazol-5- yl}pyridin-4- amine ¹H-NMR (300 MHz,DMSO-d₆): δ [ppm] = 0.86-0.73 (m, 2H), 0.94-1.05 (m, 2H), 1.27 (t, 3H),1.55-1.72 (m, 1H), 2.24 (s, 3H), 4.02 (q, 2H), 5.37 (s, 2H), 6.67-6.75(m, 2H), 7.38-7.52 (m, 2H), 8.11- 8.32 (m, 2H), 9.70 (br. s., 1H), 13.45(br. s., 1H).

Example 2-4-1 Preparation of ethyl4-({3-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-1-(2-methoxyethyl)-1H-1,2,4-triazol-5-yl}amino)nicotinate

150 mg of3-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-1-(2-methoxyethyl)-1H-1,2,4-triazol-5-amine1-8-1 (0.35 mmol, 1.0 eq.) were dissolved in 1.3 mL DMF. 85 mg of ethyl4-chloronicotinate hydrochloride (0.38 mmol, 1.1 eq.), 339 mg cesiumcarbonate (1.04 mmol, 3.0 eq.), 7.8 mg of palladium(II) acetate (0.035mmol, 0.1 eq.) and 30 mg of4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.052 mmol, 0.15 eq.)were added under an argon atmosphere. The reaction mixture was stirredin a sealed tube at 105° C. for 3 h. After cooling to ambienttemperature water and ethyl acetate were added. The layers wereseparated and the aqueous layer was extracted with ethyl acetate twice.The combined organic layers were dried over a silicon filter,concentrated in vacuo and the residue was purified by chromatography toyield the desired compound in 96% purity (3 mg, 1%).

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.69-0.75 (m, 2H), 0.99-1.06 (m, 2H),1.30 (t, 3H), 1.36 (t, 3H), 1.63-1.76 (m, 1H), 2.23 (s, 3H), 3.25 (s,3H), 3.67 (t, 2H), 4.04 (q, 2H), 4.26 (t, 2H), 4.39 (q, 2H), 5.35 (s,2H), 6.71-6.79 (m, 2H), 8.05 (d, 1H), 8.49 (d, 1H), 8.96 (s, 1H), 10.55(s, 1H).

Example 2-5-1 Preparation ofN-{3-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-1-(2-methoxyethyl)-1H-1,2,4-triazol-5-yl}pyridin-4-amine

49 mg of3-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-1-(2-methoxyethyl)-1H-1,2,4-triazol-5-amine1-11-1 (75% pure, 0.086 mmol, 1.0 eq.) were dissolved in 0.33 mL DMF. 18mg of 4-bromopyridine hydrochloride (0.094 mmol, 1.1 eq.), 84 mg cesiumcarbonate (0.26 mmol, 3.0 eq.), 1.9 mg of palladium(II) acetate (0.009mmol, 0.1 eq.) and 7.4 mg of4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.013 mmol, 0.15 eq.)were added under an argon atmosphere. The reaction mixture was stirredin a sealed tube at 105° C. overnight. After cooling to ambienttemperature the reaction mixture was diluted with DMSO and purified byHPLC to yield the desired compound in 90% purity (23 mg, 48%, 0.04mmol).

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=1.25 (t, 3H), 3.21 (s, 3H), 3.73 (t,2H), 4.00 (q, 2H), 4.39 (t, 2H), 5.64 (s, 2H), 6.68-6.78 (m, 2H), 7.26(t, 1H), 7.46 (t, 1H), 7.62 (d, 2H), 7.74 (d, 1H), 8.25 (d, 1H), 8.36(d, 2H), 9.52 (br. s., 1H).

The following compounds were prepared according to the same procedurefrom the indicated starting materials (SM=starting material):

2-5-2 SM = 1-11-2

N-{5-[1-(4- ethoxy-2,6- difluorobenzyl)- 1H-indazol-3-yl]- 1-(2-methoxyethyl)- 1H-1,2,4-triazol- 3-yl}pyridin-4- amine ¹H-NMR (300 MHz,DMSO-d₆): δ [ppm] = 1.26 (t, 3H), 3.09 (s, 3H), 3.70 (t, 2H), 4.01 (q,2H), 4.73 (t, 2H), 5.69 (s, 2H), 6.69-6.78 (m, 2H), 7.33 (t, 1H),7.44-7.51 (m, 2H), 7.51- 7.62 (m, 1H), 7.87 (d, 1H), 8.24-8.33 (m, 3H),9.88 (s, 1H).

Example 2-6-1 Preparation ofN-{1-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-1H-pyrazol-4-yl}pyrimidin-4-amine

90 mg of1-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-1H-pyrazol-4-amine1-14-1 (0.24 mmol, 1.0 eq.) were dissolved in 1.9 mL DMF. 41 mg of4-chloropyrimidine hydrochloride (0.27 mmol, 1.1 eq.), 238 mg cesiumcarbonate (0.73 mmol, 3.0 eq.), 5.5 mg of palladium(II) acetate (0.024mmol, 0.1 eq.) and 21 mg of4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.037 mmol, 0.15 eq.)were added under an argon atmosphere. The reaction mixture was stirredin a sealed tube at 105° C. overnight. After cooling to ambienttemperature water and dichloromethane were added. The layers wereseparated and the aqueous layer was extracted with dichloromethane threetimes. The combined organic layers were washed with water and brine,dried over a silicon filter, concentrated in vacuo and the residue waspurified by chromatography to yield the desired compound in 97% purity(11 mg, 10%, 0.02 mmol).

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=1.28 (t, 3H), 4.02 (q, 2H), 5.62 (s,2H), 6.71-6.79 (m, 3H), 7.18-7.29 (m, 1H), 7.46-7.56 (m, 1H), 7.75 (d,1H), 7.90 (d, 1H), 8.15-8.28 (m, 2H), 8.67 (d, 2H), 9.84 (s, 1H).

Example 2-7-1 Preparation ofN-{3-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-1,2,4-thiadiazol-5-yl}-pyridin-4-amine

43 mg of 3-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-1,2,4-thiadiazol-5-amine1-16-1 (0.13 mmol, 1.0 eq.) were suspended in 1 mL of DMF. To thismixture 47 mg of 4-bromopyridine hydrobromide (1:1) (0.20 mmol, 1.5eq.), 129 mg cesium carbonate (0.40 mmol, 3.0 eq.), 3.0 mg ofpalladium(II) acetate (0.013 mmol, 0.1 eq.) and 11.5 mg of4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.020 mmol, 0.15 eq.)were added under an argon atmosphere. The reaction mixture was stirredin a sealed tube at 105° C. for 3 hours and then at room temperatureovernight. The crude mixture was filtered over a 2 g SiO₂-cartridge,washed with methanol, concentrated in vacuo and the residue was purifiedby chromatography to yield the desired compound in 98% purity (12 mg,23%, 0.03 mmol).

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=5.83 (s, 2H), 7.12 (m, 2H), 7.21 (m,1H), 7.4629-7.37 (m, 2H), 7.48 (m, 1H), 7.54-7.61 (m, 2H), 7.79 (d, 1H),8.38 (d, 1H), 8.50 (m, 2H), 11.52 (s, 1H).

Biological Investigations

The following assays can be used to illustrate the commercial utility ofthe compounds according to the present invention.

Examples were tested in selected biological assays one or more times.When tested more than once, data are reported as either average valuesor as median values, wherein

-   -   the average value, also referred to as the arithmetic mean        value, represents the sum of the values obtained divided by the        number of times tested, and    -   the median value represents the middle number of the group of        values when ranked in ascending or descending order. If the        number of values in the data set is odd, the median is the        middle value. If the number of values in the data set is even,        the median is the arithmetic mean of the two middle values.

Examples were synthesized one or more times. When synthesized more thanonce, data from biological assays represent average values calculatedutilizing data sets obtained from testing of one or more syntheticbatch.

Biological Assay 1.0: Bub1 Kinase Assay

Bub1-inhibitory activities of compounds described in the presentinvention were quantified using a time-resolved fluorescence energytransfer (TR-FRET) kinase assay which measures phosphorylation of thesynthetic peptide Biotin-Ahx-VLLPKKSFAEPG (SEQ ID No. 1) (C-terminus inamide form), purchased from e.g. Biosyntan (Berlin, Germany) by the(recombinant) catalytic domain of human Bub1 (amino acids 704-1085),expressed in Hi5 insect cells with an N-terminal His6-tag and purifiedby affinity- (Ni-NTA) and size exclusion chromatography.

In a typical assay 11 different concentrations of each compound (0.1 nM,0.33 nM, 1.1 nM, 3.8 nM, 13 nM, 44 nM, 0.15 μM, 0.51 μM, 1.7 μM, 5.9 μMand 20 μM) were tested in duplicate within the same microtiter plate. Tothis end, 100-fold concentrated compound solutions (in DMSO) werepreviously prepared by serial dilution (1:3.4) of 2 mM stocks in a clearlow volume 384-well source microtiter plate (Greiner Bio-One,Frickenhausen, Germany), from which 50 nL of compounds were transferredinto a black low volume test microtiter plate from the same supplier.Subsequently, 2 μL of Bub1 (the final concentration of Bub1 was adjusteddepending on the activity of the enzyme lot in order to be within thelinear dynamic range of the assay: typically˜200 ng/mL were used) inaqueous assay buffer [50 mM Tris/HCl pH 7.5, 10 mM magnesium chloride(MgCl₂), 200 mM potassium chloride (KCl), 1.0 mM dithiothreitol (DTT),0.1 mM sodium ortho-vanadate, 1% (v/v) glycerol, 0.01% (w/v) bovineserum albumine (BSA), 0.005% (v/v) Trition X-100 (Sigma), 1× CompleteEDTA-free protease inhibitor mixture (Roche)] were added to thecompounds in the test plate and the mixture was incubated for 15 min at22° C. to allow pre-equilibration of the putative enzyme-inhibitorcomplexes before the start of the kinase reaction, which was initiatedby the addition of 3 μL 1.67-fold concentrated solution (in assaybuffer) of adenosine-tri-phosphate (ATP, 10 μM final concentration) andpeptide substrate (1 μM final concentration). The resulting mixture (5μL final volume) was incubated at 22° C. during 60 min., and thereaction was stopped by the addition of 5 μL of an aqueous EDTA-solution(50 mM EDTA, in 100 mM HEPES pH 7.5 and 0.2% (w/v) bovine serum albumin)which also contained the TR-FRET detection reagents (0.2 μMstreptavidin-XL665 [Cisbio Bioassays, Codolet, France] and 1 nManti-phosho-Serine antibody [Merck Millipore, cat. #35-001] and 0.4 nMLANCE EU-W1024 labeled anti-mouse IgG antibody [Perkin-Elmer, productno. AD0077, alternatively a Terbium-cryptate-labeled anti-mouse IgGantibody from Cisbio Bioassays can be used]). The stopped reactionmixture was further incubated 1 h at 22° C. in order to allow theformation of complexes between peptides and detection reagents.Subsequently, the amount of product was evaluated by measurement of theresonance energy transfer from the Eu-chelate-antibody complexrecognizing the Phosphoserine residue to the streptavidin-XL665 bound tothe biotin moiety of the peptide. To this end, the fluorescenceemissions at 620 nm and 665 nm after excitation at 330-350 nm weremeasured in a TR-FRET plate reader, e.g. a Rubystar or Pherastar (bothfrom BMG Labtechnologies, Offenburg, Germany) or a Viewlux(Perkin-Elmer) and the ratio of the emissions (665 nm/622 nm) was takenas indicator for the amount of phosphorylated substrate. The data werenormalised using two sets of (typically 32-) control wells for high-(=enzyme reaction without inhibitor=0%=Minimum inhibition) and low-(=all assay components without enzyme=100%=Maximum inhibition) Bub1activity. 1050 values were calculated by fitting the normalizedinhibition data to a 4-parameter logistic equation (Minimum, Maximum,1050, Hill; Y=Max+(Min−Max)/(1+(X/IC50)Hill)).

Biological Assay 2.0: Proliferation Assay:

Cultivated tumor cells (cells were ordered from ATCC) were plated at adensity of 3000 cells/well in a 96-well multititer plate in 200 μL ofgrowth medium supplemented 10% fetal calf serum. After 24 hours, thecells of one plate (zero-point plate) were stained with crystal violet(see below), while the medium of the other plates was replaced by freshculture medium (200 μL), to which the test substances were added invarious concentrations (0 μM, as well as in the range of 0.001-10 μM;the final concentration of the solvent dimethyl sulfoxide was 0.5%).

The cells were incubated for 4 days in the presence of test substances.Cell proliferation was determined by staining the cells with crystalviolet: the cells were fixed by adding 20 μL/measuring point of an 11%glutaric aldehyde solution for 15 minutes at room temperature. Afterthree washing cycles of the fixed cells with water, the plates weredried at room temperature. The cells were stained by adding 100μL/measuring point of a 0.1% crystal violet solution (pH 3.0). Afterthree washing cycles of the stained cells with water, the plates weredried at room temperature. The dye was dissolved by adding 100μL/measuring point of a 10% acetic acid solution. Absorbtion wasdetermined by photometry at a wavelength of 595 nm. The change of cellnumber, in percent, was calculated by normalization of the measuredvalues to the absorbtion values of the zero-point plate (=0%) and theabsorbtion of the untreated (0 μm) cells (=100%). The IC₅₀ values weredetermined by means of a 4 parameter fit.

Tab. 1. Compounds had been evaluated in the HeLa human cervical cancercell line to demonstrate antiproliferative activity.

The following table gives the data regarding Bub1 kinase inhibition, andinhibition of HeLa cell proliferation, for the examples of the presentinvention for the biological assays 1 and 2:

TABLE 1 Compounds had been evaluated in the HeLa human cervical cancercell line to demonstrate antiproliferative activity. The following tablegives the data regarding Bub1 kinase inhibition, and inhibition of HeLacell proliferation, for the examples of the present invention for thebiological assays 1 and 2: Biological Assay 2: Biological Assay 1:Proliferation assay Example Bub1 kinase assay (HeLa cell line) No.median IC₅₀ [mol/l] median IC₅₀ [mol/l] 2-1-1 6.8E−7 nd 2-1-22.0E−5 >1.0E−5 2-1-3 1.1E−6 >1.0E−5 2-1-4 3.4E−8 nd 2-1-5 3.0E−7  5.7E−6 2-2-1 2.0E−5 nd 2-3-1 3.9E−7   3.5E−6 2-3-2 1.2E−8 >1.0E−52-3-3 2.2E−8 >1.0E−5 2-3-4 8.2E−8 nd 2-4-1 9.1E−8 nd 2-5-1 1.3E−8 nd2-5-2 6.0E−7 nd 2-6-1 2.6E−8 >1.0E−5 2-7-1 2.2E−6   9.1E−6

1. A compound of formula (I)

in which

represents a

 group, whereby the * is the point of attachment, wherein X¹ is NR¹⁸, O,or S, X² is CR⁴, or N, X³ is NR¹⁸, O, or S, X⁴ is CR⁴, or N, X⁵ is CR⁴,or N, X⁶ is CR⁴, X⁷ is NR¹⁸, X⁸ is CR⁴, X⁹ is NR¹⁸, O, or S, X¹⁰ is CR⁴,or N, X¹¹ is CR⁴, or N, X¹² is CR⁴, or N, in which group E represents a

 group, whereby the * is the point of attachment, T is CH, CR¹⁷ or N, Yis CH, CR¹⁷ or N, whereby one or both of T and Y represent CH or CR¹⁷,and R¹/R² are independently from each other hydrogen, or halogen, R³ isindependently from each other 1-6C-alkyl, 1-6C-alkoxy, halogen,2-6C-alkenyl, 3-6C-cycloalkyl, 1-6C-haloalkoxy, or —C(O)OH, n is 0, 1, 2or 3, or R³ is -(1-6C-alkylene)-S—R¹⁴, -(1-6C-alkylene)-S(O)—R¹⁴,-(1-6C-alkylene)-S(O)₂—R¹⁴, -(1-6C-alkylene)-S(═O)(═NR¹⁵)R¹⁴,—O-(1-6C-alkylene)-S—R¹⁴, —O-(1-6C-alkylene)-S(O)—R¹⁴,—O-(1-6C-alkylene)-S(O)₂—R¹⁴, or —O-(1-6C-alkylene)-S(═O)(═NR¹⁵)R¹⁴, andn is 1, R⁴ is independently from each other (a) hydrogen, (b) hydroxy,(c) 1-6C-alkoxy optionally substituted with (c1) 1 or 2 hydroxy, (c2)—NR⁹R¹⁰, (c3) —S—R¹⁴, (c4) —S(O)—R¹⁴, (c5) —S(O)₂—R¹⁴, (c6)—S(═O)(═NR¹⁵)R¹⁴, (c7) —S(O)₂NR⁹R¹⁰, (d)

 whereby the * is the point of attachment, (e)

 whereby the * is the point of attachment, (f) cyano, or (g)—S(O)₂-(1-4C-alkyl), R⁵ is (a) hydrogen, (b) 2-6C-hydroxyalkyl, (c)

 whereby the * is the point of attachment, (d) —C(O)-(1-6C-alkyl), (e)—C(O)-(1-6C-alkylene)-O-(1-6C-alkyl), or (f)—C(O)-(1-6C-alkylene)-O-(1-6C-alkylene)-O-(1-6C-alkyl), R⁶ isindependently from each other halogen, cyano, C(O)NR¹¹R¹², or C(O)OR¹³,m is 0, 1, or 2, R⁷ is hydrogen, halogen, cyano, 1-6C-alkyl,2-6C-alkenyl, 1-6C-alkoxy, 1-6C-haloalkoxy, 3-6C-cycloalkyl, C(O)NR¹¹R¹²or NR⁹R¹⁰, R⁸ is hydrogen, halogen, cyano, 1-6C-alkyl, 2-6C-alkenyl,1-6C-alkoxy, 1-6C-haloalkoxy, 3-6C-cycloalkyl or NR⁹R¹⁰, or R⁷ and R⁸form together with the two carbon atoms to which they are attached a6-membered aromatic ring, which is optionally substituted independentlyone or more times with halogen or 1-3C-alkyl, or R⁷ and R⁸ form togethera n-propylene or a n-butylene group, R⁹, R¹⁰ are independently from eachother hydrogen, 1-6C-alkyl or together with the nitrogen atom to whichthey are attached form a 4-6-membered heterocyclic ring optionallycontaining one further heteroatom selected from the group consisting ofO, S or N, R¹¹, R¹² are independently from each other hydrogen,1-6C-alkyl, 2-6C-hydroxyalkyl, or (1-4C-alkyl)-S(O)₂-(1-4C-alkyl), R¹³is independently from each other hydrogen or 1-4C-alkyl, R¹⁴ isindependently from each other a group selected from 1-6C-alkyl,3-7C-cycloalkyl, phenyl and benzyl, wherein said group is optionallysubstituted with one or two or three substituents, identically ordifferently, selected from the group of hydroxy, halogen, or —NR⁹R¹⁰,R¹⁵ is independently from each other hydrogen, cyano, or —C(O)R¹⁸, R¹⁶is 1-6C-alkyl, or 1-6C-haloalkyl, R¹⁷ is independently from each otherhalogen, cyano, —C(O)NR¹¹R¹², or —C(O)OR¹³, R¹⁸ is (a) hydrogen, (b)1-6C-alkyl optionally substituted with (b1) 1 or 2 hydroxy, (b2)1-6C-alkoxy, (b3) —C(O)OR¹³, (b4) —C(O)NR¹¹R¹², (b5) —NR⁹R¹⁰, (b6)—S—R¹⁴, (b7) —S(O)—R¹⁴, (b8) —S(O)₂—R¹⁴, (b9) —S(═O)(═NR¹⁵)R¹⁴, (b10)—S(O)₂NR⁹R¹⁰, (c) —S(O)₂-(1-4C-alkyl), (d) —C(O)-(1-6C-alkyl), or anN-oxide, a salt, a tautomer or a stereoisomer of said compound, or asalt of said N-oxide, tautomer or stereoisomer.
 2. The compoundaccording to claim 1, wherein

represents a

 group, whereby the * is the point of attachment, wherein X¹ is NR¹⁸, O,or S, X² is CR⁴, or N, X³ is NR¹⁸, O, or S, X⁴ is CR⁴, or N, X⁵ is CR⁴,or N, X⁶ is CR⁴, X⁷ is NR¹⁸, X⁸ is CR⁴, X⁹ is NR¹⁸, O, or S, X¹⁰ is CR⁴,or N, X¹¹ is CR⁴, or N, X¹² is CR⁴, or N, in which group E represents a

 group, whereby the * is the point of attachment, T is CH, CR¹⁷ or N, Yis CH, CR¹⁷ or N, whereby one or both of T and Y represent CH or CR¹⁷,and R¹/R² are independently from each other hydrogen, or halogen, R³ isindependently from each other 1-3C-alkoxy, n is 0, 1, 2, or 3, or R³ is-(1-4C-alkylene)-S—R¹⁴, -(1-4C-alkylene)-S(O)—R¹⁴,-(1-4C-alkylene)-S(O)₂—R¹⁴, -(1-4C-alkylene)-S(═O)(═NR¹⁵)R¹⁴,—O-(1-4C-alkylene)-S—R¹⁴, —O-(1-4C-alkylene)-S(O)—R¹⁴,—O-(1-4C-alkylene)-S(O)₂—R¹⁴, or —O-(1-4C-alkylene)-S(═O)(═NR¹⁵)R¹⁴, andn is 1, R⁴ is independently from each other (a) hydrogen, (b) hydroxy,(c) 1-4C-alkoxy optionally substituted with (c1) 1 or 2 hydroxy, (c2)—NR⁹R¹⁰, (c3) —S—R¹⁴, (c4) —S(O)—R¹⁴, (c5) —S(O)₂—R¹⁴, (c6)—S(═O)(═NR¹⁵)R¹⁴, (c7) —S(O)₂NR⁹R¹⁰, (f) cyano, or (g)—S(O)₂-(1-4C-alkyl), R⁵ is hydrogen, R⁶ is independently from each otherhalogen, cyano, —C(O)NR¹¹R¹², or —C(O)OR¹³, m is 0, 1, or 2, R⁷ ishydrogen, halogen, cyano, 1-3C-alkyl, 2-3C-alkenyl, 1-3C-alkoxy,1-3C-haloalkoxy, 3-6C-cycloalkyl, —C(O)NR¹¹R¹² or —NR⁹R¹⁰, R⁸ ishydrogen, halogen, cyano, 1-3C-alkyl, 2-3C-alkenyl, 1-3C-alkoxy,1-3C-haloalkoxy, 3-6C-cycloalkyl or —NR⁹R¹⁰, or R⁷ and R⁸ form togetherwith the two carbon atoms to which they are attached a 6-memberedaromatic ring, which is optionally substituted independently one or moretimes with halogen or 1-3C-alkyl, R⁹, R¹⁰ are independently from eachother hydrogen or 1-3C-alkyl, or together with the nitrogen atom towhich they are attached form a 4-6-membered heterocyclic ring optionallycontaining one further heteroatom selected from the group consisting ofO, S or N, R¹¹, R¹² are independently from each other hydrogen,1-3C-alkyl, or 2-3C-hydroxyalkyl, R¹³ is independently from each otherhydrogen or 1-3C-alkyl, R¹⁴ is independently from each other a groupselected from 1-3C-alkyl, and 3-7C-cycloalkyl, R¹⁵ is independently fromeach other hydrogen, cyano, or —C(O)R¹⁶, R¹⁶ is methyl, ortrifluoromethyl, R¹⁷ is independently from each other halogen, cyano,—C(O)NR¹¹R¹², or —C(O)OR¹³, R¹⁸ is (a) hydrogen, (b) 1-4C-alkyloptionally substituted with (b1) 1 or 2 hydroxy, (b2) 1-3C-alkoxy, (b3)—C(O)OR¹³, (b4) —C(O)NR¹¹R¹², (b5) —NR⁹R¹⁰, (b6) —S—R¹⁴, (b7) —S(O)—R¹⁴,(b8) —S(O)₂—R¹⁴, (b9) —S(═O)(═NR¹⁵)R¹⁴, (b10) —S(O)₂NR⁹R¹⁰, (c)—S(O)₂-(1-4C-alkyl), (d) —C(O)-(1-3C-alkyl), or an N-oxide, a salt, atautomer or a stereoisomer of said compound, or a salt of said N-oxide,tautomer or stereoisomer.
 3. The compound according to claim 1, wherein

represents a

 group, whereby the * is the point of attachment, wherein X¹ is NR¹⁸, O,or S, X² is CR⁴, or N, X³ is NR¹⁸, O, or S, X⁴ is CR⁴, or N, X⁵ is CR⁴,or N, X⁶ is CR⁴, X⁷ is NR¹⁸, X⁸ is CR⁴, X⁹ is NR¹⁸, O, or S, X¹⁰ is CR⁴,or N, X¹¹ is CR⁴, or N, X¹² is CR⁴, or N, in which group E represents a

 group, whereby the * is the point of attachment, T is CH, CR¹⁷ or N, Yis CH, CR¹⁷ or N, whereby one or both of T and Y represent CH or CR¹⁷,and R¹/R² are independently from each other hydrogen, or halogen, R³ is1-3C-alkoxy, n is 0, or 1, R⁴ is independently from each other (a)hydrogen, (c) 1-4C-alkoxy optionally substituted with (c1) hydroxy, (c3)—S—R¹⁴, (c4) —S(O)—R¹⁴, (c5) —S(O)₂—R¹⁴, (c6) —S(═O)(═NR¹⁵)R¹⁴, or (c7)—S(O)₂NR⁹R¹⁰, R⁵ is hydrogen, R⁶ is —C(O)NR¹¹R¹², or —C(O)OR¹³, m is 0,or 1, R⁷ is 3-6C-cycloalkyl, R⁸ is 1-3C-alkyl, or R⁷ and R⁸ formtogether with the two carbon atoms to which they are attached a6-membered aromatic ring, which is optionally substituted independentlyone or more times with halogen or 1-3C-alkyl, R⁹, R¹⁰ are independentlyfrom each other hydrogen or 1-3C-alkyl, or together with the nitrogenatom to which they are attached form a 4-6-membered heterocyclic ringoptionally containing one further heteroatom selected from the groupconsisting of O, S or N, R¹¹, R¹² are independently from each otherhydrogen, or 1-3C-alkyl, R¹³ is independently from each other hydrogenor 1-3C-alkyl, R¹⁴ is 1-3C-alkyl, R¹⁵ is hydrogen, R¹⁸ is (a) hydrogen,(b) 1-4C-alkyl optionally substituted with (b1) hydroxy, (b2)1-3C-alkoxy, (b3) —C(O)OR¹³, (b4) —C(O)NR¹¹R¹², (b5) —NR⁹R¹⁰, (b6)—S—R¹⁴, (b7) —S(O)—R¹⁴, (b8) —S(O)₂—R¹⁴, (b9) —S(═O)(═NR¹⁵)R¹⁴, (d)—C(O)-(1-3C-alkyl), or an N-oxide, a salt, a tautomer or a stereoisomerof said compound, or a salt of said N-oxide, tautomer or stereoisomer.4. The compound according to claim 1, wherein

represents a

 group, whereby the * is the point of attachment, wherein X¹ is NR¹⁸, orS, X² is CR⁴, or N, X³ is NR¹⁸, X⁴ is N, X¹⁰ is CR⁴, X¹¹ is CR⁴, X¹² isN, in which group E represents a

 group, whereby the * is the point of attachment, T is CH, Y is CH, orN, and R¹/R² are independently from each other hydrogen, or fluoro, R³is ethoxy, n is 0, or 1, R⁴ is (a) hydrogen, R⁵ is hydrogen, R⁶ is—C(O)OR¹³, m is 0, or 1, R⁷ is cyclopropyl, R⁸ is methyl, or R⁷ and R⁸form together with the two carbon atoms to which they are attached a6-membered aromatic ring, R⁹, R¹⁰ together with the nitrogen atom towhich they are attached form a morpholine ring R¹³ is independently fromeach other hydrogen or ethyl, R¹⁴ is methyl, R¹⁸ is (a) hydrogen, (b)1-2C-alkyl optionally substituted with (b1) hydroxy, (b2) methoxy, (b3)—C(O)OR¹³, (b5) —NR⁹R¹⁰, (b8) —S(O)₂—R¹⁴, (d) acetyl, or an N-oxide, asalt, a tautomer or a stereoisomer of said compound, or a salt of saidN-oxide, tautomer or stereoisomer.
 5. The compound according to claim 1,which is selected from the group consisting of:5′-cyclopropyl-1′-(4-ethoxy-2,6-difluorobenzyl)-4′-methyl-1-[2-(morpholin-4-yl)ethyl]-N-(pyrimidin-4-yl)-1H, 1′H-3,3′-bipyrazol-5-amine,1-[5′-cyclopropyl-1′-(4-ethoxy-2,6-difluorobenzyl)-4′-methyl-5-(pyrimidin-4-ylamino)-1H,1′H-3,3′-bipyrazol-1-yl]ethanone,[5′-cyclopropyl-1′-(4-ethoxy-2,6-difluorobenzyl)-4′-methyl-5-(pyrimidin-4-ylamino)-1H,1′H-3,3′-bipyrazol-1-yl]acetic acid,5′-cyclopropyl-1′-(4-ethoxy-2,6-difluorobenzyl)-1,4′-dimethyl-N-(pyrimidin-4-yl)-1H, 1′H-3,3′-bipyrazol-5-amine,N-{3-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-1-(2-methoxyethyl)-1H-1,2,4-triazol-5-yl}pyrimidin-4-amine,5′-cyclopropyl-1′-(4-ethoxy-2,6-difluorobenzyl)-4′-methyl-1-[2-(methylsulfonyl)ethyl]-N-(pyrimidin-4-yl)-1H, 1′H-3,3′-bipyrazol-5-amine,5′-cyclopropyl-1′-(4-ethoxy-2,6-difluorobenzyl)-1,4′-di-methyl-N-(pyridin-4-yl)-1H,1′H-3,3′-bipyrazol-5-amine,N-{3-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-1-(2-methoxyethyl)-1H-1,2,4-triazol-5-yl}pyridin-4-amine,2-{3-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-5-(pyridin-4-ylamino)-1H-1,2,4-triazol-1-yl}ethanol,N-{3-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl}pyridin-4-amine,ethyl4-({3-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-1-(2-methoxyethyl)-1 H-1,2,4-triazol-5-yl}amino)nicotinate,N-{3-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-1-(2-methoxyethyl)-1H-1,2,4-triazol-5-yl}pyridin-4-amine,N-{5-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl}pyridin-4-amine,N-{1-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-1H-pyrazol-4-yl}pyrimidin-4-amine, andN-{3-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-1,2,4-thiadiazol-5-yl}pyridin-4-amine,or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, ora salt of said N-oxide, tautomer or stereoisomer.
 6. (canceled)
 7. Amethod for the treatment of a hyperproliferative disease or a disorderresponsive to induction of cell death comprising administering to apatient in need thereof a therapeutically effective amount of a compoundaccording to claim 1, or an N-oxide, a salt, a tautomer or astereoisomer of said compound, or a salt of said N-oxide, tautomer orstereoisomer.
 8. The method according to claim 7, wherein thehyperproliferative disease armor disorder responsive to induction ofcell death is a haematological tumour, a solid tumour or metastasesthereof.
 9. The method according to claim 8, wherein thehyperproliferative disease is cervical cancer.
 10. A pharmaceuticalcomposition comprising a compound according to claim 1, or an N-oxide, asalt, a tautomer or a stereoisomer of said compound, or a salt of saidN-oxide, tautomer or stereoisomer, together with at least onepharmaceutically acceptable carrier or auxiliary.
 11. (canceled)
 12. Apharmaceutical combination comprising a compound according to claim 1,or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, ora salt of said N-oxide, tautomer or stereoisomer, and one or morechemotherapeutic anti-cancer agents or target-specific anti-canceragents.